Compounds that modulate PPAR activity and methods for their preparation

ABSTRACT

This invention discloses compounds that alter PPAR activity. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds of their salts, and methods of using them as therapeutic agents for treating or preventing disipidemia, hypercholesteremia, obesity, eating disorders, hyperglycemia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia and diabetes in a mammal as well as methods of suppressing appetite and modulating leptin levels in a mammal. The present invention also discloses methods for making the disclosed compounds.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. Ser. No.10/347,749, filed Jan. 22, 2003, which claims priority to U.S.Provisional Applications Ser. Nos. 60/370,508, filed Apr. 5, 2002 and60/386,026, filed Jun. 5, 2002.

FIELD OF THE INVENTION

The present invention relates to compounds and pharmaceuticalformulations that can be used to treat conditions mediated by nuclearhormone receptors, more specifically, to compounds and pharmaceuticalformulations that modulate Peroxisome Proliferator Activation Receptor(PPAR) activity.

BACKGROUND OF THE INVENTION

Hypercholesterolemia, dyslipidemia, diabetes, and obesity arewell-recognized risk factors in the onset of atherosclerosis andcoronary heart disease. The diseases are characterized by high levels ofcholesterol and lipids in the blood. The blood cholesterol pool isgenerally dependent on dietary uptake of cholesterol from the intestine,and from the biosynthesis of cholesterol throughout the body, especiallythe liver. The majority of cholesterol in plasma is carried onapolipoprotein B-containing lipoproteins, such as low-densitylipoproteins (LDL) and very-low-density lipoproteins (VLDL). The risk ofcoronary artery disease in man increases when LDL and VLDL levelsincrease. Conversely, high levels of cholesterol carried in high-densitylipoproteins (HDL) is protective against coronary artery disease (Am. J.Med., 1977;62:707-714).

The statins represent perhaps the most important class of lipid-loweringdrugs. These compounds inhibit HMG-CoA reductase which is implicated inthe rate-limiting step in cellular cholesterol biosynthesis.Representative statins include atorvastatin, lovastatin, pravastatin,and simvastatin. The effectiveness of these compounds depends on LDLreceptor regulation. Other important antilipidemia drugs includefibrates such as gemfibril and clofibrate, bile acid sequestrants suchas cholestyramine and colestipol, probucol, and nicotinic acid analogs.

To date, a number of oral antidiabetic agents have been developed. Themost commonly used hypoglygernic drugs are the sulfonylureas.Sulfonylureas are generally used to stimulate insulin. The biguanidemetformin is generally used to improve insulin sensitivity and todecrease hepatic glucose output. Acarbose is used to limit postprandialhyperglycemia. Thiazolidine 2,4 diones are used to enhance insulinaction without increasing insulin secretion.

Obesity is a chronic disease that is highly prevalent in modern societyand is associated not only with a social stigma, but also with decreasedlife span and numerous medical problems, including diabetes mellitus,insulin resistance, hypertension, hypercholesterolemia, thromboembolicdisease, and coronary heart disease. Rissanen et al, British MedicalJournal, 301:835-837 (1990). Treatment of obesity remains a problem andit is unclear whether dieting results in decreased long-term risk ofearly death. A further important obesity intervention is physicalactivity. Exercise, however, in general, has been found to be onlymoderately successful in promoting weight loss. A program combining bothdieting and exercise as well as behaviour modification is widely viewedas the optimal approach to weight loss. Studies have demonstrated thatthe combination of both food restriction and exercise promote asubstantial loss of fat while maintaining lean tissue.

Peroxisome Proliferator Activation Receptors (PPAR) are implicated in anumber of biological processes and disease states includinghypercholesterolemia, dyslipidemia, and diabetes. PPARs are members ofthe nuclear receptor superfamily of transcription factors that includessteroid, thyroid, and vitamin D receptors. They play a role incontrolling expression of proteins that regulate lipid metabolism.Furthermore, the PPARs are activated by fatty acids and fatty acidmetabolites. There are three PPAR subtypes PPAR α, PPAR β (also referredto as PPAR δ), and PPAR γ. Each receptor shows a different pattern oftissue expression, and differences in activation by structurally diversecompounds. PPAR γ, for instance, is expressed most abundantly in adiposetissue and at lower levels in skeletal muscle, heart, liver, intestine,kidney, vascular endothelial and smooth muscle cells as well asmacrophages. PPAR receptors are associated with regulation of insulinsensitivity and blood glucose levels, macrophage differentiation,inflammatory response, and cell differentiation. Accordingly, PPARs havebeen associated with obesity, diabetes, carcinogenesis, hyperplasia,atherosclerosis, dyslipidemia, and hypercholesterolemia.

In addition, PPARα agonists lower plasma triglycerides and LDLcholesterol and are therefore useful in treating hypertriglyceridemia,dyslipidemia and obesity. PPAR γ is associated with the development ofnon-insulin-dependent diabetes mellitus (NIDDM), hypertension, coronaryartery disease, dyslipidemia and certain malignancies. Finally,activation of PPAR β has been demonstrated to increase HDL levels.(Leibowitz, WO97/28149, August 1997.) More recently, a PPAR β selectiveagonist was reported to have shown a dose-related increase in serumHDL-C and decrease in LDL-C and VLDL-TG in insulin-resistant middle agedrhesus monkeys. (W. R. Oliver et al., PNAS, v. 98, pp. 5306-5311, 2001)

Antilipidemic, antidiabetic and anti-obesity agents are still consideredto have non-uniform effectiveness. The effectiveness of antidiabetic andantilipidemic therapies is limited, in part because of poor patientcompliance due to unacceptable side effects. These side effects includediarrhea and gastrointestinal discomfort, and in the case ofantidiabetics, edema, hypoglycemia and hepatoxicity. Furthermore, eachtype of drug does not work equally well in all patients.

For the reasons set forth above, there is a need for novelantilipidemic, antidiabetic, and anti-obesity agents that can be usedalone or in combination. Furthermore, activation of multiple PPARs, forinstance, PPARβ alone or in combination with the simultaneous activationof PPAR α and/or PPAR γ, may be desirable in formulating a treatment fordyslipidemia in which HDL is increased and LDL lowered.

SUMMARY OF THE INVENTION

The present invention provides compounds capable of modulating PPARactivity. Compounds of the present invention are described by Formula I:

and pharmaceutically acceptable salts thereof, where:

X⁰ and X¹ are independently absent, O, S, —CH₂—, —CH₂—CH₂—, —CH═CH—,—CH≡CH—, —S(O)₂—, or —S(O)—;

Ar¹ and Ar² are each independently unsubstituted or substituted aryl orheteroaryl, provided that Ar¹ is not thiazolyl or oxazolyl;

is absent; or when present,

is a saturated or unsaturated hydrocarbon chain which is substituted orunsubstituted, wherein said chain has from 1 to 4 atoms so that

Ar¹, X¹, (CH₂)_(r), and Ar², together form a five to eight memberedring;

R¹ and R² are selected from hydrogen, lower alkyl, lower alkoxy,haloalkyl, —O—(CH₂)_(m)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃,—S(O)_(p)alkyl, S(O)_(p)aryl, —(CH₂)_(m)OR⁵, —(CH₂)_(m)NR⁶R⁷, —COR⁵,CO₂R⁵, or —NR⁶R⁷, or together with the atoms to which they are attachedform a five to eight member ring;

R³ and R⁴ are selected from hydrogen, lower alkyl, lower alkoxy,haloalkyl, —O—(CH₂)_(m)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃,—S(O)_(p)alkyl, S(O)_(p)aryl, —(CH₂)_(m)OR⁵, —(CH₂)_(m)NR⁶R⁷, —COR⁵,—CO₂H, —CO₂R⁵, or —NR⁶R⁷;

provided that at least one of R¹-R⁴ is H, lower alkyl, lower alkoxy,haloalkyl, —O—(CH₂)_(m)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃,—S(O)_(p)alkyl, S(O)_(p)aryl, —(CH₂)_(m)OR⁵, —(CH₂)_(m)NR⁶R⁷, or NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, or aryl;

R⁶ and R⁷ are each independently hydrogen, alkyl, alkenyl, alkynyl,—COalkyl, —COaryl, cycloalkyl, —CO₂alkyl, —CO₂aryl, or R⁶ and R⁷together with the atoms to which they are attached form a 4 to 7membered ring having 1 to 3 heteroatoms;

m is 0 to 5;

p is 0, 1, or 2;

q is 0 to 6; and

r is 0 to 6.

The invention also provides a compound of formula (II):

and pharmaceutically acceptable salts thereof, where:

X⁰ and X¹ are independently absent, O, S, —CH₂—, —CH₂—CH₂—, —CH═CH—,—CH≡CH—, —S(O)₂—, or —S(O)—;

Ar¹ and Ar² are each independently unsubstituted or substituted aryl orheteroaryl, provided that Ar¹ is not thiazolyl or oxazolyl;

is absent; or when present,

is a saturated or unsaturated, hydrocarbon chain which is substituted orunsubstituted, wherein said chain has from 1 to 4 atoms so that

Ar¹, X¹, (CH₂)_(r), and Ar², together form a five to eight member ring;

R³ and R⁴ are selected from hydrogen, lower alkyl, lower alkoxy,haloalkyl, —O—(CH₂)_(m)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃,—S(O)_(p)alkyl, S(O)_(p)aryl, —(CH₂)_(m)OR⁵, —(CH₂)_(m)NR⁶R⁷, —COR⁵,—CO₂H, —CO₂R⁵, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, or aryl;

R⁶ and R⁷ are each independently hydrogen, alkyl, alkenyl, alkynyl,—COalkyl, —COaryl, cycloalkyl, —CO₂alkyl, —CO₂aryl, —SO₂alkyl, —SO₂aryl,or R⁶ and R⁷ together with the atoms to which they are attached form a 4to 7 membered ring having 1 to 3 heteroatoms;

is a saturated or unsaturated, substituted or unsubstituted hydrocarbonchain or hydrocarbon-heteroatom chain having from 3 to 6 atoms whereinthe carbon atom of position 2 is connected to the carbon atom ofposition 3 to form a five to eight member ring;

m is 0 to 5;

p is 0 to 2;

q is 0 to 6; and

r is 0 to 6.

In still another embodiment of the present invention, a method oftreating, preventing or controlling hypercholesteremia and dyslipidemiain a mammal is provided. The method comprises administering to themammal in need thereof a therapeutically effective amount of thecompounds of the present invention. Additionally, the compounds of thepresent invention are also useful in the method of the present inventionfor treating, preventing, or controlling obesity, eating disorders,hyperglycemia, atherosclerosis, hypertriglyceridemia, hyperinsulinemiaand diabetes. Furthermore, the compounds of the present invention arealso useful in the methods of suppressing appetite in a mammal,modulating leptin levels in a mammal, and treating a patient exhibitingglucose disorders associated with circulating glucocorticoids, growthhormone, catecholamines, glucagon, or parathyroid hormone. For eachdisease state treatable, preventable, or controllable by the method ofthe present invention, a therapeutically effective amount of thecompounds of the present invention are administered to the mammal inneed thereof.

In yet another embodiment of the present invention, a method forpreparing compounds with Formulae I-II, or a pharmaceutically acceptablesalt thereof, is provided. The method of this embodiment comprisesreacting

in a solvent in the presence of a base such as cesium carbonate: with

where

X⁰ is OH or SH;

n, q, r, R¹, R², R³, R⁴, X¹,

Ar¹ and Ar₂ are as defined above for Formula I;

R¹¹ is a lower alkyl; and

X is a halogen.

In yet another embodiment of the present invention, an alternativemethod for preparing compounds with Formulae I-II, or a pharmaceuticallyacceptable salt thereof, is provided. The method of this embodimentcomprises reacting

where X is a halide, R¹-R⁴ have any of the meanings defined above, andR¹¹ is a lower alkyl with:

where - - - is a bond or is absent and wherein n, q, r, X⁰, X¹,

Ar¹ and Ar² are as defined above for Formula I;

in the presence of a catalyst such as a palladium catalyst to form

where - - - is a bond or is absent.

The double bond may optionally be removed, for instance, byhydrogenation and the resulting ester is preferably hydrolyzed to formthe compounds of Formulas I or II.

In still another embodiment, the invention provides a process forpreparing the compound of formula I-4 which is:

or a pharmaceutically acceptable salt thereof, comprising:

-   -   (a) conversion of phenol 1A to the thiocyante 1B;    -   (b) alkylation of phenol moiety of thiocyanate 1B to        acetoxyester 1C;    -   (c) reduction of the thiocyanate moiety in 1C to form thiol 1D;    -   (d) alkylation of thiol 1D with chloride 3C to form 4a;    -   (e) saponification of the ester moiety in 4a to form I-4;        where

R¹ is hydrogen or together with R² forms a 5 membered carbocyclic ring;

R² is methoxy or together with R¹ forms a 5 membered carbocyclic ring;

R³ is hydrogen or methyl;

R⁴ is hydrogen;

X¹ is absent or O; and

r is 0 or 1.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc.denote both straight and branched groups; but reference to an individualradical such as “propyl” embraces only the straight chain radical, abranched chain isomer such as “isopropyl” being specifically referredto.

The term “alkyl” as used herein refers to a straight or branched,hydrocarbon of from 1 to 11 carbon atoms and includes, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl group can also besubstituted with one or more of the substituents selected from loweralkoxy, lower thioalkoxy, —O(CH₂)₁₋₅CF₃, halogen, nitro, cyano, ═O, ═S,—OH, —SH, —CF₃, —OCF₃, —CO₂H, CO₂C₁-C₆alkyl, —NH₂, —NHC₁-C₆alkyl,—CONR′R″, or —N(C₁-C₆alkyl)₂ where R′ and R″ are independently alkyl,akenyl, alkynyl, aryl, or joined together to form a 4 to 7 memberingring. Preferred alkyl groups have from 1 to 6 carbon atoms (C₁-C₆alkyl).

The term “lower alkyl” as used herein refers to a subset of alkyl whichmeans a straight or branched hydrocarbon radical having from 1 to 6carbon atoms and includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,and the like. Optionally, herein lower alkyl is referred to as“C₁-C₆alkyl.”

The term “haloalkyl” as used herein refers to a lower alkyl radical, asdefined above, bearing at least one halogen substituent, for example,chloromethyl, fluoroethyl, trifluoromethyl, or 1,1,1-trifluoroethyl andthe like. Haloalkyl can also include perfluoroalkyl wherein allhydrogens of a loweralkyl group are replaced with fluorine atoms.

The term “alkenyl” means a straight or branched unsaturated hydrocarbonradical having from 2 to 12 carbon atoms and includes, for example,ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl,2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,3-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl,and the like.

The term “alkynyl” means a straight or branched hydrocarbon radicalhaving from 2 to 12 carbon atoms having at least one triple bond andincludes, for example, 1-propynyl, 1-butynyl, 3-butynyl, 1-pentynyl,3-pentynyl, 3-methyl-3-butynyl, 1-hexynyl, 3-hexynyl, 3-heptynyl,1-octynyl, 1-nonynyl, 1-decynyl, 1-undecynyl, 1-dodecynyl, and the like.

The term “alkylene” as used herein refers to a divalent group derivedfrom a straight or branched chain saturated hydrocarbon having from 1 to10 carbon atoms by the removal of two hydrogen atoms, for example,methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene,2,2-dimethylpropylene, and the like. The alkylene groups of thisinvention can be optionally substituted. The alkylene group can also besubstituted with one or more of the substituents selected from loweralkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)₁₋₅CF₃, halogen, nitro,cyano, ═O, ═S, —OH, —SH, —CF₃, —CO₂H, —CO₂C₁-C₆alkyl, —NH₂,—NHC₁-C₆alkyl, —CONR′R″, or —N(C₁-C₆alkyl)₂ where R′ and R″ areindependently alkyl, akenyl, alkynyl, aryl, or joined together to form a4 to 7 member ring. Preferred alkylene groups have from 1 to 6 carbonatoms (C₁-C₆ alkyl).

The term “cycloalkyl” means a hydrocarbon ring containing from 3 to 12carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cycloctyl, decalinyl, norpinanyl, andadamantyl. Where possible, the cycloalkyl group may contain doublebonds, for example, 3-cyclohexen-1-yl. The cycloalkyl ring may beunsubstituted or substituted by 1 to 3 substituents selected from alkyl,alkoxy, thioalkoxy, hydroxy, thiol, nitro, halogen, amino, alkyl anddialkylamino, formyl, carboxyl, CN, —NH—CO—R′, —CO—NHR′—, —CO₂R′, —COR′,aryl, or heteroaryl, wherein alkyl, aryl, and heteroaryl are as definedherein. Examples of substituted cycloalkyl groups includefluorocyclopropyl, 2-iodocyclobutyl, 2,3-dimethylcyclopentyl,2,2-dimethoxycyclohexyl, and 3-phenylcyclopentyl.

The term “heteroatom” as used herein represents oxygen, nitrogen, orsulfur (O, N, or S) as well as sulfoxyl or sulfonyl (SO or SO₂) unlessotherwise indicated.

The term “heterocycloalkyl” means a monocyclic, fused, bridged, or spirobicyclic heterocyclic ring systems. Monocyclic heterocyclic ringscontain from about 3 to 12 ring atoms, with from 1 to 5 heteroatomsselected from N, O, and S, and preferably from 3 to 7 member atoms, inthe ring. Bicyclic heterocyclics contain from 7 to 17 member atoms,preferably 7 to 12 member atoms, in the ring. Bicyclic heterocyclicscontain from about 7 to about 17 ring atoms, preferably from 7 to 12ring atoms. Bicyclic heterocyclics rings may be fused, spiro, or bridgedring systems. Examples of heterocyclic groups include cyclic ethers(oxiranes) such as ethyleneoxide, tetrahydrofuran, dioxane, andsubstituted cyclic ethers, wherein the substituents are those describedabove for the alkyl and cycloalkyl groups. Typical substituted cyclicethers include propyleneoxide, phenyloxirane (styrene oxide),cis-2-butene-oxide (2,3-dimethyloxirane), 3-Chlorotetrahydrofuran,2,6-dimethyl-1,4-dioxane, and the like. Heterocycles containing nitrogenare groups such as pyrrolidine, piperidine, piperazine,tetrahydrotriazine, tetrahydropyrazole, and substituted groups such as3-aminopyrrolidine, 4-methylpiperazin-1-yl, and the like. Typical sulfurcontaining heterocycles include tetrahydrothiophene,dihydro-1,3-dithiol-2-yl, and hexahydrothiepin-4-yl. Other commonlyemployed heterocycles include dihydro-oxathiol-4-yl,tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl,tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl,morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl,octahydrobenzofuranyl, octahydrobenzimidazolyl, andoctahydrobenzothiazolyl. For heterocycles containing sulfur, theoxidized sulfur heterocycles containing SO or SO₂ groups are alsoincluded. Examples include the sulfoxide and sulfone forms oftetrahydrothiophene.

The term “hydrocarbon chain” as used herein refers to a straighthydrocarbon of from 2 to 6 carbon atoms. The hydrocarbon chain isoptionally substituted with one or more substituents selected from loweralkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)₀₋₂CF₃, halogen, nitro,cyano, ═O, ═S, —OH, —SH, —CF₃, —CO₂H, —CO₂(C₁-C₆alkyl), —NH₂,—NHC₁-C₆alkyl, —CONR′R″, or —N(C₁-C₆alkyl)₂ where R′ and R″ areindependently alkyl, akenyl, alkynyl, aryl, or joined together to form a4 to 7 member ring.

The term “aryl” means a cyclic or polycyclic aromatic ring having from 5to 12 carbon atoms, and being unsubstituted or substituted with up to 4groups selected from C₁-C₆alkyl, cycloalkyl, heteroaryl,dialkylaminoalkoxy, or those recited above as substituents for alkyl.The term aryl includes both monovalent species, for example when Ar₂ isaryl, and divalent species, for example where Ar₁ is aryl. Examples ofaryl groups include, but are not limited to, phenyl, biphenyl, naphthyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl,2-chloro-5-methylphenyl, 3-chloro-2-methylphenyl,3-chloro-4-methylphenyl, 4-chloro-2-methylphenyl,4-chloro-3-methylphenyl, 5-chloro-2-methylphenyl, 2,3-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl,3,4-dimethylphenyl, 4-trifluoromethyl and the like.

The term “heteroaryl” means an aromatic mono-, bi-, or or polycyclicring incorporating one or more (i.e. 1-4) heteroatoms selected from N,O, and S. The term heteroaryl includes both monovalent species, forexample where Ar₂ is heteroaryl, and divalent species, for example whereAr₁ is heteroaryl. It is understood that a heterocycle is optionallysubstituted with up to 4 groups selected from C₁-C₆ alkyl, cycloalkyl,heteroaryl, dialkylaminoalkoxy, or those recited above as substituentsfor alkyl. Examples of suitable monocyclic heteroaryl include, but arenot limited to substituted or unsubstituted thienyl, furanyl, pyrrolyl,imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl, tetrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, pyrrolidinyl,piperazinyl, azetidinyl, aziridinyl, morpholinyl, thietanyl, oxetaryl.Preferred monocyclic diheterocycles include, but are not limited to 1-,2-, 4-, or 5-imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 3-, 4-, or5-isothiazolyl, 3-, 4-, or 5-isoxazolyl, 1,3-, or 5-triazolyl, 1-, 2-,or 3-tetrazolyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 1- or2-piperazinyl, 2-, 3-, or 4-morpholinyl. Examples of suitable bicyclicand polyclic heteroaryl groups include but are not limited to includebut are not limited to 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-,4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-,6-, or 7-indolyl, 2-, 3-,4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-,3-, 4-, 6-, 7-, 8-, or 9-quinolinzinyl, 2-, 3-, 4-, 5-, 6-, 7-, or8-quinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-,7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-,6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-,6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl,1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-,or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl,1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-,8-, or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenanthrolinyl,1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-,9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-, or10phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-,or 10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-,6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-,or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl,2-, 4-, or 5-4H-imidazol[4,5-d]thiazolyl, 3-, 5-, or8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl,1-, 3-, 6-, 7-, 8-, or 9-furo[3, 4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-,7-, 8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-,5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroaryl groupsinclude, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl.

The term “hydrocarbon-heteroatom chain” as used herein refers to ahydrocarbon chain wherein one or more carbon atoms are replaced with aheteroatom. The hydrocarbon-heteroatom chain is optionally substitutedwith one or more substituents selected from lower alkyl, lower :alkoxy,lower thioalkoxy, —O(CH₂)₀₋₂CF₃, halogen, nitro, cyano, ═O, ═S, —OH,—SH, —CF₃, —CO₂H, —CO₂C₁-C₆alkyl, —NH₂, —NHC₁-C₆alkyl, —CONR′R″, or—N(C₁-C₆alkyl)₂ where R′ and R″ are independently alkyl, akenyl,alkynyl, aryl, or joined together to form a 4 to 7 member ring.

The term “heteroalkylene” as used herein, refers to an alkylene radicalas defined above, that includes one or more heteroatoms such as oxygen,sulfur, or nitrogen (with valence completed by hydrogen or oxygen) inthe carbon chain or terminating the carbon chain.

The terms “lower alkoxy” and “lower thioalkoxy” as used herein refers toO-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for“lower alkyl.”

The term “cycloalkenyl” means a cycloalkyl group having one or morecarbon-carbon double. Example includes cyclobutene, cyclopentene,cyclohexene, cycloheptene, cyclobutadiene, cyclopentadiene, and thelike.

The symbol “

” means a bond to a group wherein a 4 to 8 membered ring is formed.Typically this symbol will appear in pairs.

When a bond is represented by a line such as “- - - ” this is meant torepresent that the bond may be absent or present provided that theresultant compound is stable and of satisfactory valency.

The term “patient” means all mammals including humans. Examples ofpatients include, humans, cows, dogs, cats, goats, sheep, pigs, andrabbits.

A “therapeutically effective amount” is an amount of a compound of thepresent invention that when administered to a patient ameliorates asymptom of dyslipidemia, non-insulin dependent diabetes mellitus,obesity, hyperglycemia, hypercholesteremia, hyperlipidemia,atherosclerosis, hypertriglyceridemia, hyperinsulinemia, glucosedisorders associated with circulating glucocorticoids, growth hormone,catecholamines, glucagon, or parathyroid hormone. Additionally, a“therapeutically effective amount” is an amount of a compound of thepresent invention that when administered to a patient ameliorates asymptom of an eating disorder suppresses appetite, or modulates leptinlevels.

The term “a pharmaceutically acceptable salt” refers to the relativelynon-toxic, inorganic and organic base or acid addition salts ofcompounds of the present invention. These salts can be prepared in situduring the final isolation and purification of the compounds or byseparately reacting the purified compound in its free form with asuitable organic or inorganic base or acid and isolating the salt thusformed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate,palmitate, stearate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylatemesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, andthe like. These also include cations based on the alkali and alkalineearth metals, such as sodium, lithium, potassium, calcium, magnesium,and the like, as well as non-toxic ammonium, quaternary ammonium, andamine cations including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. (See, forexample, Berge S. M., et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977;66:1-19, which is incorporated herein by reference.) The free baseform may be regenerated by contacting the salt form with a base. Whilethe free base may differ from the salt form in terms of physicalproperties, such as solubility, the salts are equivalent to theirrespective free bases for the purposes of the present invention.

Compounds of the present invention are described by Formula I:

and pharmaceutically acceptable salts thereof, wherein:

X⁰ and X¹ are independently absent, O, S, —CH₂—, —CH₂—CH₂—, —CH═CH—,—CH≡CH—, —S(O)₂—, or —S(O)—;

Ar¹ and Ar² are each independently unsubstituted or substituted aryl orheteroaryl, provided that Ar¹ is not thiazolyl or oxazolyl;

is absent; or when present,

is a saturated or unsaturated hydrocarbon chain which is substituted orunsubstituted, wherein said chain has from 1 to 4 atoms so that

Ar¹, X¹, (CH₂)_(r), and Ar², together form a five to eight memberedring;

R¹ and R² are selected from hydrogen, lower alkyl, lower alkoxy,haloalkyl, —O—(CH₂)_(m)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃,—S(O)_(p)alkyl, S(O)_(p)aryl, —(CH₂)_(m)OR⁵, —(CH₂)_(m)NR⁶R⁷, —COR⁵,CO₂R⁵, or —NR⁶R⁷, or together with the atoms to which they are attachedform a five to eight member ring;

R³ and R⁴ are selected from hydrogen, lower alkyl, lower alkoxy,haloalkyl, —O—(CH₂)_(m)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃,—S(O)_(p)alkyl, S(O)_(p)aryl, —(CH₂)_(m)OR⁵, —(CH₂)_(m)NR⁶R⁷, —COR⁵,—CO₂H, —CO₂R⁵, or —NR⁶R⁷;

provided that at least one of R₁-R₄ is H, lower alkyl, lower alkoxy,haloalkyl, —O—(CH₂)_(m)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃,—S(O)_(p)alkyl, S(O)_(p)aryl, —(CH₂)_(m)OR⁵, —(CH₂)_(m)NR⁶R⁷, or NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, or aryl;

R⁶ and R are each independently hydrogen, alkyl, alkenyl, alkynyl,—COalkyl, —COaryl, cycloalkyl, —CO₂alkyl, —CO₂aryl, or R⁶ and R⁷together with the atoms to which they are attached form a 4 to 7membered ring having 1 to 3 heteroatoms;

m is 0 to 5;

p is 0, 1, or 2;

q is 0 to 6; and

r is 0 to 6.

In compounds of Formula I, R¹, R², R³, and R⁴ are preferably selectedfrom hydrogen, alkyl, or alkoxy. More preferably, R² and R³ arehydrogen; and R¹ and R⁴ are alkyl or alkoxy. In a particularly preferredembodiment of Formula I, R² and R³ are hydrogen; R¹ is alkyl; and R⁴ isalkoxy. Preferred alkoxy include methoxy, ethoxy, isopropoxy, n-propoxy,t-butoxy, n-butoxy, or isobutoxy. Similarly, preferred alkyl includemethyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, or isobutyl. In amost preferred embodiment of Formula I, q is 1, Ar¹ is phenyl, X¹ isabsent, r is 0, V¹ is absent, and Ar² is 4-trifluoromethylphenyl.

In compounds of Formula I,

is preferably (CH₂)_(t) wherein t is 1 to 4. Additionally,

is optionally substituted with at least one substituent, wherein thesubstituent include but are not limited to lower alkyl, lower alkoxy,lower thioalkoxy, —O(CH₂)₀₋₂CF₃, halogen, nitro, cyano, ═O, ═S, —OH,—SH, —CF₃, OCF₃, —CO₂H, —CO₂C₁-C₆alkyl, —NH₂, —NHC₁-C₆alkyl, —CONR′R″,or —N(C₁-C₆alkyl)₂ where R′ and R″ are independently alkyl, akenyl,alkynyl, aryl, or joined together to form a 4 to 7 member ring.

In a preferred embodiment of Formula I, R¹ and R² are joined together toform a five to eight member ring having Formula II. Such a ringincludes, for example, cycloalkyl, aryl, heterocycloalkyl, or aheteroaryl rings where each such ring is optionally substituted asdescribed above.

and pharmaceutically acceptable salts thereof, wherein:

X⁰ and X¹ are independently absent, O, S, —CH₂—, —CH₂—CH₂—, —CH═CH—,—CH≡CH—, —S(O)₂—, or —S(O)—;

Ar¹ and Ar² are each independently unsubstituted or substituted aryl orheteroaryl, provided that Ar¹ is not thiazolyl or oxazolyl;

is absent; or when present,

a saturated or unsaturated hydrocarbon chain which is substituted orunsubstituted, wherein said chain has from 1 to 4 atoms so that

Ar¹, X¹, (CH₂)_(r), and Ar², together form a five to eight memberedring;

R³ and R⁴ are selected from hydrogen, lower alkyl, lower alkoxy,haloalkyl, —O—(CH₂)_(m)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃,—S(O)_(p)alkyl, S(O)_(p)aryl, —(CH₂)_(m)OR⁵, —(CH₂)_(m)NR⁶R⁷, —COR⁵,—CO₂H, —CO₂R⁵, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, or aryl;

R⁶ and R⁷ are each independently hydrogen, alkyl, alkenyl, alkynyl,—COalkyl, —COaryl, cycloalkyl, —CO₂alkyl, —CO₂aryl, —SO₂alkyl, —SO₂aryl,or R⁶ and R⁷ together with the atoms to which they are attached form a 4to 7 membered ring having 1 to 3 heteroatoms;

is a saturated or unsaturated, substituted or unsubstituted hydrocarbonchain or hydrocarbon-heteroatom chain having from 3 to 6 atoms whereinthe carbon atom of position 2 is connected to the carbon atom ofposition 3 to form a five to eight member ring;

m is 0 to 5;

p is 0 to 2;

q is 0 to 6; and

r is 0 to 6.

Preferably,

is —CH₂CH₂CO—O—, —CH₂—CH₂—O—CO—, —CH₂—CH₂—CH₂—CH₂—, —HC═CH—HC═CH—,—N═CH—HC═CH—, —HC═N—HC═CH—, —HC═CH—N═CH—, —HC═CH—HC═N—, —CH₂—CH₂—CH₂—,—CH₂—CH₂—O—CH₂—, —CH₂—O—CH₂CH₂—, —CH₂—HC═CH—CH₂—, —CH₂—HC═CH—, —CH₂CH₂—NR⁴—CH₂—, —COCH═CH—O—, —O—CH═CH—CO—, —CH═CH—NR⁴—, —NR⁴—CH═CH—,—CH═CH—CH₂—, —CH₂—CH₂—NR⁴—, —NR⁴—CH₂—CH₂—, —O—CH₂—CH₂—, —CH₂—CH₂—O—,—CH₂—CH₂CO—, —CH₂—CO—CH₂—, —CO—CH₂—CH₂—, —CH₂—CH₂—CH₂—CO—,—CO—CH₂—CH₂—CH₂—, —CH₂—CO—CH₂—CH₂—, —CH₂—CH₂—CO—CH₂, —CH₂—CH₂—CH₂—NR⁴—,—NR⁴—CH₂—CH₂—CH₂—, —O—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—, —CO—NR⁴—CH₂—CH₂—,NR⁴CO—CH₂—CH₂—, —CH₂—CH₂NR⁴—CO—, or —CH₂—CH₂—CO—NR⁴—. It will beunderstood that the left-most atom of these groups in attached to theatom labeled “3” in Formula I and the right-most atom of these groups isattached to the atom label “2” in Formula I.

In the present embodiment,

optionally substituted with 1 or more substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower thioalkoxy,—O(CH₂)₁₋₅CF₃, halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF₃, —CO₂H,—CO₂C₁-C₆alkyl, —N₂, —NHC₁-C₆alkyl, —OCH₂O—, and —N(C₁-C₆alkyl)₂.

In compounds of Formula II, R³, and R⁴ are preferably selected fromhydrogen, alkyl, or alkoxy. More preferably, R³ and R⁴ are hydrogen; and

is a saturated or unsaturated, unsubstituted hydrocarbon chain havingfrom 3 to 6 atoms wherein the carbon atom of position 2 is connected tothe carbon atom of position 3 to form a five to eight member ring suchas a cyclopentyl or cyclohexyl ring. In a most preferred embodiment ofFormula II, q is 1, Ar¹ is phenyl, X¹ is O, r is 1, V¹ is absent, andAr² is 4-trifluoromethylphenyl.

Also in this embodiment,

is preferably (CH₂)_(t) wherein t is 1 to 4. Additionally,

is optionally substituted with at least one substituent, wherein thesubstituent include but are not limited to lower alkyl, lower alkoxy,lower thioalkoxy, —O(CH₂)₀₋₂CF₃, halogen, nitro, cyano, ═O, ═S, —OH,—SH, —CF₃, —OCF₃, —CO₂H, —CO₂C₁-C₆alkyl, —NH₂, —NHC₁-C₆alkyl, —CONR′R″,or —N(C₁-C₆alkyl)₂ where R′ and R″ are independently alkyl, akenyl,alkynyl, aryl, or joined together to form a 4 to 7 member ring.

Examples of compounds of Formula I and Formula II include

[4-(Biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid;

[4-(Biphenyl-4-ylmethylsulfanyl)-2-methyl-phenoxy]-acetic acid;

[2-Methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

[5-Methoxy-2-methyl-4-(2′,4′,6′-trimethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

[4-(4′-Chloro-3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-2-methyl-phenoxy]-aceticacid;

[4-(2′,4′-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid;

[4-(3′,4′-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid;

[5-Methoxy-2-methyl-4-(3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

[4-(4′-Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid;

[5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

[7-(4′-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid;

[4-(4Benzyloxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid;

{5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid;

{2-Methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid;

[5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid;

[4-(9H-Fluoren-2-ylmethylsulfanyl-2-methyl-phenoxy]-acetic acid;

{[5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid;

{5-Methoxy-2-methyl-4-[6-4-trifluoromethyl-phenyl)-pyridin-3-ylmethylsulfanyl]-phenoxy}-aceticacid;

[5-Chloro-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

[3-Methoxy-4-(4′-trifluoromethyl-biphenyl)-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

{2-Methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}-aceticacid;

{5-Methoxy-2-methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}-aceticacid;

{2-Methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-vinyl]-phenoxy}-aceticacid;

{2-Methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)ethyl]-phenoxy}-aceticacid;

{7-[4-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

[5-Methyl-7-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid;

(4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benzylsulfanyl}-5-methoxy-2-methyl-phenoxy)-aceticacid;

{2-Methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid;

{4-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid;

{4-[4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid;

{4-[4-(4-Methoxy-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid;

{4-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid;

{2-Methyl-4-[4-(4-trifluoromethoxy-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid;

{6-Methyl-8-[4-(5-trifluoromethyl-pyridine-2-yl)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid;

{5-Chloro-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid;

[5-hydroxy-2-methyl-4,4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

[5-Methoxy-2-methyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

{7-[4-(4-trifluoromethyl-benzyl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-methoxy-2-methyl-phenoxy}-aceticacid;

{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid;

{5-Methoxy-2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid;

{7-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid;

{2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid;

{5-Methoxy-2-methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid;

[2-Methyl-4-(4-phenoxy-benzylsulfanyl)-phenoxy]-acetic acid;

[7-(4′-Trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid;

[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid;

[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethanesulfonyl)-phenoxy]-aceticacid;

[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethanesulfinyl)-phenoxy]-aceticacid;

[2-Propyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

{7-[3-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

(5-Methoxy-2-methyl-4-{2-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-ethylsulfanyl}-phenoxy)-aceticacid;

[7-(4′-Trifluoromethyl-biphenyl-2-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid;

{5-Methoxy-2-methyl-4-[2-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid;

{4-[4-(4-Fluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid;

{4-[4-(4-Chloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid;

4-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-2methyl-phenoxy]-aceticacid;

{2-Methyl-4-[4-(pyridine-2-ylmethoxy)-benzylsulfanyl]-phenoxy}-aceticacid;

{5-Chloro-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid;

{7-[4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{5-Methoxy-7-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[4-(4-Fluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[4-(4-Methoxy-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid;

[7-(4-Benzyloxy-benzylsulfanyl)-indan-4-yloxy]-acetic acid;

{7-[4-(4-Chloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid;

{7-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[4-(3,4-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[4-(4-Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[4-(4-Fluoro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[4-(4-Trifluoromethoxy-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[4-(4-Fluoro-2-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[4-(3,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[4-Methoxy-3-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[3-(4-Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[2-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[3,5-Dichloro-4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{8-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid;

{8-[3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid;

{8-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid;

{8-[4-(5-Trifluoromethyl-pyridine-2-yl)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid;

{7-[5-(2-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[3-(2,6-Dichloro-phenyl)-5-methyl-isoxazol-4-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[3-(4-Trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[2-(4′-Trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[2-(4′-Trifluoromethyl-biphenyl-4-yl)-ethyl]-indan-4-yloxy}-aceticacid;

{5-Methyl-7-[4-5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-2,3-dihydro-benzofuran-4yloxy}-aceticacid;

[8-(4′-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-chroman-5-yloxy]-aceticacid;

{8-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-chroman-5-yloxy}-aceticacid;

{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid;

{7-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid;

{7-[3-(4-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid;

{5-Chloro2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid;

2-[2-butyl-4-({4-[4-(trifluoromethyl)phenyl]-phenyl}methylthio)phenoxy]aceticacid;

{6-methyl-8-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid;

{4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-aceticacid;

(4-{2-Butyl-5-chloro-1-[4-(1-cyano-cyclopentyl)-benzyl]-1H-imidazol-4-ylmethylsulfanyl}-2-methyl-phenoxy)-aceticacid;

[4-(5-Biphenyl-4-yl-2-thiophen-2-yl-4,5-dihydro-oxazol-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid;

{4-[2-(4-Bromo-phenoxy)-ethylsulfanyl]-2,6-dimethyl-phenoxy}-aceticacid;

[4-(3-{2-[4(2-Diethylamino-ethoxy)-phenyl]-benzimidazol-1-yl}-propylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid;

[4-(5-Biphenyl-2-thiophen-2-yl-4,5-dihydro-oxazol-4-ylmethylsulfanyl)-2-methyl-phenoxy]-aceticacid;

(4-{2-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-7-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid;

{2-Methyl-4-[2-(5-phenyl-naphthalen-1-yloxy)ethylsulfanyl]-phenoxy}-acetic acid;

[2-Methyl-4-(3-phenoxy-benzylsulfanyl)-phenoxy]-acetic acid;

[2,5-Dimethyl-4-(5-p-tolyl-1,3,4-oxadiazol-2-ylmethylsulfanyl)-phenoxy]-aceticacid;

[2-Methyl-4-(4-pyrazol-1-yl-benzylsulfanyl)-phenoxy]-acetic acid;

[2-Methyl-4-(5-methyl-3-phenyl-isoxazol-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

[4-(Biphenyl-2-ylmethylsulfanyl)-2-methyl-phenoxy]-acetic acid;

{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid;

[2-Methyl-4-(5-p-tolyl-1,3,4-oxadiazol-2-ylmethylsulfanyl)-phenoxy]-aceticacid;

{4-[3-(4-Chloro-phenyl)-1,2,4-oxadiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid;

[2,5-Dimethyl-4-(4-pyrazol-1-yl-benzylsulfanyl)-phenoxy]-acetic acid;

[4-(Biphenyl-2-ylmethylsulfanyl)-2,5-dimethyl-phenoxy]-acetic acid;

[4-(4-Benzyloxy-benzylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-aceticacid;

[4-(4-Benzyloxy-benzylsulfanyl)-2,6-dimethyl-phenoxy]-acetic acid;

[4-(4-Benzyloxy-benzylsulfanyl)-2,5-dimethyl-phenoxy]-acetic acid;

[4-(4-Benzyloxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid;

[4-(4-Benzyloxy-benzylsulfanyl)-phenoxy]-acetic acid;

[4-(Biphenyl-4-ylmethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-aceticacid;

[4-(Biphenyl-4-ylmethylsulfanyl)-2,6-dimethyl-phenoxy]-acetic acid;

[4-(Biphenyl-4-ylmethylsulfanyl)-2,5-dimethyl-phenoxy]-acetic acid;

[4-(Biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid;

{4-[3-(2-Fluoro-phenoxy)-benzylsulfanyl]-2,6-dimethyl-phenoxy}-aceticacid;

[4-(2-{4-[2-(3-Chloro-4-cyclohexyl-phenyl)-ethyl]-piperazin-1-yl}-ethylsulfanyl)-2-methyl-phenoxy]-aceticacid;

[5-Methoxy-2-methyl-4-(2-{4-[2-(3-phenyl-benzofuran-7-yl)-ethyl]-piperazin-1-yl}-ethylsulfanyl)-phenoxy]-aceticacid;

{4-[2-(2,6-Diphenyl-piperidin-1-yl)-ethylsulfanyl]-5-methoxy-2-methyl-phenoxy}-aceticacid;

[2-Methyl-4-(2-{4-[2-(3-phenyl-benzofuran-7-yl)-ethyl]-piperazin-1-yl}-ethylsulfanyl)-phenoxy]-aceticacid;

{4-[2-(2,6-Diphenyl-piperidin-1yl)-ethylsulfanyl]-2-methyl-phenoxy}-aceticacid;

and pharmaceutically acceptable salts thereof.

A subset of exemplary compounds of Formula I and Formula II include

[4-(Biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid;

[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

[4-(2′,4′-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid;

[5-Methoxy-2-methyl-4-(3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

[4-(4′-Fluorobiphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid;

[7-(4′-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid;

{5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid;

[5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid;

{{5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid;

{5-Methoxy-2-methyl-4-[6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethylsulfanyl]-phenoxy}-aceticacid;

[3-Methoxy-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

{5-Methoxy-2-methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}-aceticacid;

(4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benzylsulfanyl}-5-methoxy-2-methyl-phenoxy)-aceticacid;

[5-Methoxy-2-methyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;

{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-methoxy-2-methyl-phenoxy}-aceticacid;

{5-Methoxy-2-methyl4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid;

{5-Methoxy-2-methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid;

[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid;

{7-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid;

{5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-2,3-dihydro-benzofuran-4-yloxy}-aceticacid;

and pharmaceutically acceptable salts thereof.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R or S configuration.The present invention includes all diastereomeric, enantiomeric, andepimeric forms as well as the appropriate mixtures thereof.Stereoisomers may be obtained, if desired, by methods known in the artas, for example, the separation of stereoisomers by chiralchromatographic columns. Additionally, the compounds of the presentinvention may exist as geometric isomers. The present invention includesall cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers aswell as the appropriate mixtures thereof

In some situations, compounds may exist as tautomers. All tautomers areincluded within Formulas I and II and are provided by this invention.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The present invention includes all pharmaceutically acceptable,non-toxic esters of the compounds of Formulae I and II. Such estersinclude C₁-C₆ alkyl esters where the alkyl group is a straight orbranched chain. Acceptable esters also include C₅-C₇ cycloalkyl estersas well as arylalkyl esters such as, but not limited to benzyl. C₁-C₄esters are preferred. Esters of the compounds of the present inventionmay be prepared according to conventional methods.

The compounds of the present invention are suitable to be administeredto a patient for the treatment, control, or prevention ofhypercholesteremia, dyslipidemia, obesity, hyperglycemia,hypercholesteremia, atherosclerosis, hypertriglyceridemia, andhyperinsulinemia. The compounds of the present invention are alsosuitable to be administered to a patient for the suppression of appetiteand modulation of leptin. Accordingly, the compounds may be administeredto a patient alone or as part of a composition that contains othercomponents such as excipients, diluents, and carriers, all of which arewell-known in the art. The compositions can be administered to humansand/or animals either orally, rectally, parenterally (intravenously,intramuscularly, or subcutaneously), intracisternally, intravaginally,intraperitoneally, intravesically, locally (powders, ointments, ordrops), or as a buccal or nasal spray.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil), and injectable organic esters suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid; (b) binders, as for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain complex silicates, and sodiumcarbonate; (e) solution retarders, as for example paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, as for example, kaolin and bentonite; and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar, as well as high molecular weight polyethyleneglycols, andthe like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well-known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are preferably suppositorieswhich can be prepared by mixing the compounds of the present inventionwith suitable non-irritating excipients or carriers such as cocoabutter, polyethyleneglycol, or a suppository wax, which are solid atordinary temperatures, but liquid at body temperature and therefore,melt in the rectum, or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

The compounds of the present invention can be administered to a patientat dosage levels in the range of about 0.1 to about 2,000 mg per day.For a normal human adult having a body weight of about 70 kilograms, adosage in the range of about 0.01 to about 10 mg per kilogram of bodyweight per day is preferable. However, the specific dosage used canvary. For example, the dosage can depend on a numbers of factorsincluding the requirements of the patient, the severity of the conditionbeing treated, and the pharmacological activity of the compound beingused. The determination of optimum dosages for a particular patient iswell-known to those skilled in the art.

PREPARATION OF COMPOUNDS OF THE INVENTION

The present invention contains compounds that can be synthesized in anumber of ways familiar to one skilled in organic synthesis. Thecompounds outlined herein can be synthesized according to the methodsdescribed below, along with methods typically utilized by a syntheticchemist, and combinations or variations of those methods, which aregenerally known to one skilled in the art of synthetic chemistry. Thesynthetic route of compounds in the present invention is not limited tothe methods outlined below. It is assumed one skilled in the art will beable to use the schemes outlined below to synthesize compounds claimedin this invention. Individual compounds may require manipulation of theconditions in order to accommodate various functional groups. A varietyof protecting groups generally known to one skilled in the art may berequired. Purification, if necessary, can be accomplished on a silicagel column eluted with the appropriate organic solvent system. Also,reverse phase HPLC or recrystallization may be employed.

Many of the compounds with Formulas I and II are preferably made byreacting:

in a solvent in the presence of a base such as cesium carbonate, withthe aryl halide:

wherein:

n, R¹, R², R³, R⁴, X⁰, X¹, V¹, Ar¹, and Ar² are the same as definedabove for Formula I;

R¹¹ is a lower alkyl; and

X is a halogen.

The resulting ester is then preferably hydrolyzed to form the compoundsof Formulas I and II. Specifically, compounds of Formulas I and II canbe prepared using the synthetic route outlined in Scheme 1-6.

Scheme 1 covers the preparation of compounds of Formulas I and IIwherein X⁰ is S, q is 0-3,

is absent, X¹ is absent and r is 0. Compounds of the general formula Aare thiocyanated with a mixture of bromine and sodium thiocyanate togive compounds of the general formula B. Compounds of the generalformula B are then alkylated with an alkyl haloacarboxylate to givecompounds of the general formula C. The preferred alkyl haloacarboxylateis methyl bromoacetate. Alternate routes to compounds of formula C willbe readily apparent to a person skilled in the art of organic synthesis.Compounds of the general formula D are then prepared by reduction of Cwith dithiothreitol in methanol. Compounds of the general formula D arethen alkylated with compounds of the general formula Y in the samemanner as for B to give E. Compounds of the general formula Y areprepared as described in Scheme 7 (below) or are readily available fromcommercial sources. Compounds of the general formula E are then,saponified with LiOH in the THF to give the final compound F.

Scheme 2 covers the preparation of compounds of Formula I-II wherein X⁰is O, q is 0-3, X¹ is absent,

is absent, and r is 0. Compounds of the general formula A are alkylatedwith an alkyl haloacarboxylate to give compounds of the general formulaG. The preferred alkyl halocarboxylate is methyl bromoacetate. Alternateroutes to compounds of formula G when Y is O will be readily apparent toa person skilled in the art of organic synthesis. Compounds of thegeneral formula G are then acylated using Friedel-Crafts conditions togive compounds of the general formula H which are then oxidized withm-chloroperoxybenzoic acid followed by hydrolysis to give phenoliccompounds of the general formula I. Compounds of the general formula Iare then reacted in a similar manner as for D to give aftersaponification with LiOH in THF, compounds of the general formula K.

Scheme 3 covers the preparation of compounds of formula I-II wherein X⁰is —CH₂—CH₂—, —C═C—, q is 0-3, X¹ is absent,

is absent, and r is 0. Compounds of the general formula A are brominatedwith bromine, using acetic acid as solvent to give L. Alternatively,N-bromosuccinimide may be used in place of bromine and dichloromethanein place of acetic acid as solvent. Compounds of the general formula Lare then alkylated with an alkyl haloacarboxylate to give compounds ofthe general formula M. The preferred alkyl halocarboxylate is methylbromoacetate. Alternate routes to compounds of formula M will be readilyapparent to a person skilled in the art of organic synthesis. Compoundsof the general formula M are then reacted in the presence of tetrakis(triphenylphosphine)palladium(0) and biphenyl compounds of the generalformula EE to give compounds of the general formula N. Compounds of thegeneral formula EE are prepared as described in Scheme 9 or are readilyavailable from commercial sources. Compounds of the general formula Nare then saponified with LIOH in THF to give the final compound O.

Scheme 4 covers the preparation of compounds of formula I-II wherein X⁰is —CH₂—CH₂—, q is 0-3, X¹ is absent,

is absent, and r is 0. Accordingly, compounds of the general N can bereduced with hydrogen and palladium as catalyst to give compounds of thegeneral formula P which are then saponified LiOH in THF to give thefinal compound Q.

Scheme 5 covers the preparation of compounds of formula I-II wherein X⁰is absent, q is 0, X¹ is absent,

is absent, and r is 0 are prepared. Compounds of the general formula Mare allowed to react with tetrakis (triphenylphosphine) palladium(0) andbiphenyl compounds of the general formula HH to give compounds of thegeneral formula R. Compounds of the general formula HH are prepared asdescribed in Scheme 10 or are readily available from commercial sources.Compounds of the general formula R are then saponified with LiOH in THFto give the final compound S.

With reference to Scheme 6, compounds of formula I-II wherein X⁰ is S orO, q is 1-3, X¹ is O, and r is 1-3 are prepared using the sameconditions utilized for the preparation of K.

With reference to Scheme 7, compounds of the general formula X areprepared by reacting aryl boronic acid W with aryl bromide V in thepresence of Pd(0) and cesium carbonate. Compounds of the general formulaX are then reacted with methanesulfonyl chloride to give chlorides ofthe general formula Y.

With reference to Scheme 8, compounds of the general formula CC areprepared wherein an appropriate hydroxy benzyl alcohol AA is alkylatedwith an appropriate bromide Z. The resulting compound BB is then reactedwith methanesulfonyl chloride to give chlorides of the general formulaCC.

With reference to Scheme 9, compounds of the general formula EE areprepared by reacting aryl boronic acid V with aryl bromide DD in thepresence of Pd(0) and cesium carbonate.

With reference to Scheme 10, compounds of the general formula HH areprepared by reacting aryl bromide V with boronic acid FF to give GG.Compounds of the general formula GG are then reacted with an alkyllithium reagent and then quenched with a borate which is hydrolyzed togive compounds of the general formula HH.

With reference to Scheme 11, compounds of formula I-II wherein X⁰ is Sor O, q is 1-3, X¹ is absent, r is O, and V¹ is a saturated orunsaturated hydrocarbon chain which is substituted or unsubstituted areprepared using the same conditions utilized for the preparation of K.Compounds of the general formula NN are prepared as described in Scheme12 or are readily available from commercial sources.

With reference to Scheme 12, compounds of the general formula NN can beprepared by reacting an appropriately substituted aryl amine LL underSandmeyer conditions followed by heating to give intermediate MM. Theresulting intermediate MM is then reacted with methanesulfonyl chlorideto give chlorides of the general formula NN.

Not all compounds of Formulas I-II falling into a given class may becompatible with some of the reaction conditions described. Suchrestrictions are readily apparent to those skilled in the art of organicsynthesis, and alternative methods must then be used.

The following non-limiting descriptions also demonstrate methods for thesynthesis of compounds of Formulae I and II.

EXAMPLE 1

Synthesis of [4-(Biphenyl-4ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acid (compound 1)

Step 1. Preparation of 5-Methoxy-2-methyl-phenol (compound 1A)

2-Hydroxy-4-methoxy-benzaldehyde (3 g, 19.7 mmol), ammonium formate (6.2g, 99 mmol) and palladium/carbon (900 mg @10%) were added to 26 mlglacial acetic acid and heated at 110° C. for 1 h. The reaction wascooled, filtered, and diluted with water (100 ml). The crude product wasextracted with chloroform (3×50 ml), washed with water, brine, and driedover anhydrous sodium sulfate. The resulting solution was concentratedand used for the next step without further purification. MS m/z 139(M+1).Step 2. Preparation of 5-Methoxy-2-methyl-4-thiocyanato-phenol (compound1B)

The product from Example 1A (3.5 g, 25 mmol), sodium thiocyanate (6.48g, 80 mmol), and sodium bromide (2.6 g, 25 mmol) were dissolved in 30 mlanhydrous methanol. Bromine (4.4 g, 28 mmol) was added drop wise over 15minutes and allowed to stir at ambient temperature for 1 h. Brine wasadded (50 ml) and the crude product was extracted into ethyl acetate(3×100 ml). The combined organic extracts were washed with brine, driedover anhydrous sodium sulfate, decanted, and concentrated to afford thetitle product in good purity. 400 MHz ¹H NMR (DMSO-d₆) δ 10.13 (s, 1H),7.25 (s, 1H), 6.54 (s, 1H), 3.77 (s, 3H), 2.0 (s, 3H); MS m/z 196 (M+1).Step 3. Preparation of (5-Methoxy-2-methyl-4-thiocyanato-phenoxy)-aceticacid methyl ester (compound 1C)

The product from Example 1B (620 mg, 3.2 mmol), methyl bromoacetate (854mg, 3.5 mmol), and cesium carbonate (3.1 g, 9.6 mmol) were stirred in 10ml anhydrous acetonitrile at ambient temperature for 1 h. The reactionwas filtered through Celite®, concentrated, and purified using normalphase chromatography. 400 MHz ¹H NMR (DMSO-d₆) δ 7.33 (s, 1H), 6.72 (s,1H), 4.93 (s, 2H), 3.84 (s, 3H), 3.66 (s, 3H), 2.09 (s, 3H); MS m/z 268(M+1).Step 4. Preparation of (4Mercapto-5-methoxy-2-methyl-phenoxy)-aceticacid methyl ester (compound 1D)

The product from Example 1C (1.1 g, 4.1 mmol) and dithiothreitol (824mg, 5.4 mmol) were dissolved in 20 ml methanol with 2.5 ml water. Thesolution was refluxed for 4 h, cooled, concentrated, and purified bynormal phase chromatography. 400 MHz ¹H NMR (DMSO-d₆) δ 7.02 (s, 1H),6.54 (s, 1H), 4.79 (s, 2H), 4.41 (s, 1H), 3.72 (s, 3H), 3.64 (s, 3H),2.02 (s, 3H); MS m/z 243 (M+1).Step 5. Preparation of 4-Bromomethyl-biphenyl (compound 1E)

Biphenyl-4-yl methanol (500 mg, 2.72 mmol) phosphorus tribromide (809mg, 2.99 mmol), and lithium bromide (260 mg, 2.99 mmol) were dissolvedin 10 ml DMF and stirred at ambient temperature for 1 h. Water (10 ml)was added and the crude product was extracted into dichloromethane,dried over anhydrous sodium sulfate, filtered through silica gel, andconcentrated. MS m/z 167 (M+1-Br).Step 6. Preparation of[4-(Biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acidmethyl ester (compound 1F)

The product from Example 1D (100 mg, 0.38 mmol), the product fromExample 1E (92 mg, 0.38 mmol) and cesium carbonate (250 mg, 0.76 mmol)were added to 5 ml acetonitrile and stirred at ambient temperature for 4hr. The reaction was filtered through Celite®, concentrated and purifiedthrough normal phase chromatography. MS m/z 409 (M+1).Step 7. Preparation of[4-(Biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acid(compound 1)The product from Example 1F (101 mg) was dissolved in 10 ml THF/watersolution (10:1). Lithium hydroxide monohydrate (300 mg) was added andstirred for 30 minutes. 2 Normal aqueous HCl was added to pH<5 and thenwashed with ethyl acetate. The organic extract was dried over anhydroussodium sulfate, decanted, and concentrated. The title product wasrecrystallized from chloroform/hexanes. mp 60-62° C.; 400 MHz ¹H NMR(DMSO-d₆) δ 12.94 (br(s), 1H), 7.58 (d, 2H, J=8 Hz), 7.52 (d, 2H, J=8Hz), 7.39 (t, 2H, J=7.2 Hz), 7.30 (m, 3H), 7.02 (s, 1H), 6.52 (s, 1H),4.69 (s, 2H), 4.01 (s, 2H), 3.73 (s, 3H), 2.01 (s, 3H). MS m/z 393(M−1). Anal. Calc'd for C₃₂H₂₂O₄S.3H₂O C, 69.05; H, 5.07; found: C,69.04; H, 5.35.

EXAMPLE 2

Synthesis of [4-Biphenyl-4-ylmethylsulfanyl)-2-methyl-phenoxy]-aceticacid (compound 2)

Step 1. Preparation of 2-Methyl-4-thiocyanato-phenol (compound 2A)

The title compound was prepared in a manner analogous to Example 1B from2-methylphenol. 400 MHz ¹H NMR (DMSO-d₆) δ 10.09 (s, 1H), 7.36 (s, 1H),7.30 (d, 1H, J=8.1 Hz), 6.83 (d, 1H, J=8.1 Hz), 2.08 (s, 3H); MS m/z 166(M+1).Step 2. Preparation of (2-Methyl-4-thiocyanato-phenoxy)-acetic acidmethyl ester (compound 2B)

The title compound was prepared from 2 Example 2A in a manner analogousto Example 1C. 400 MHz ¹H NMR (DMSO-d₆) δ 7.46 (s, 1H), 6.95 (d, 1H,J=8.5 Hz), 6.80 (d, 1H, J=8.5 Hz), 4.86 (s, 2H), 3.65 (s, 3H), 2.17 (s,3H); MS m/z 238 (M+1).Step 3. Preparation of (4-Mercapto-2-methyl-phenoxy)-acetic acid methylester (compound 2C)

The title compound was prepared from(2-methyl-4-thiocyanato-phenoxy)-acetic acid methyl ester in a manneranalogous to Example 1C. 400 MHz ¹H NMR (DMSO-d₆) δ 7.05 (s, 1H), 7.00(d, 1H, J=10.3 Hz), 6.70 (d, 1H, J=10.3 Hz), 5.00 (s, 1H), 4.73 (s, 1H),3.63 (s, 3H), 2.09 (s, 3H); MS m/z 213 (M+1).Step 4. Preparation of[4-(Biphenyl-4-ylmethylsulfanyl)-2-methyl-phenoxy]-acetic acid methylester (compound 2D)

The title compound was prepared in the manner analogous to Example 1Fusing 2C and 1E. MS m/z 379 (M+1).Step 5. Preparation of[4-(Biphenyl-4ylmethylsulfanyl)-2-methyl-phenoxy]-acetic acid (compound2)The title compound was prepared in the manner analogous to Example 1. mp138° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 7.59 (d, 2H, J=9.5 Hz), 7.53 (d, 2H,J=9.5 Hz), 7.40 (m, 2H), 7.31 (m, 3H), 7.14 (d, 1H, J=1.7 Hz), 7.09 (d,1H, J=10.7 Hz), 6.70 (d, 1H, J=10.7 Hz), 4.62 (s, 2H), 4.11 (s, 2H),2.09 (s, 3H); MS m/z 363 (M−1).

EXAMPLE 3

Synthesis of[2-Methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 3)

Step 1. Preparation of (4′-Trifluoromethyl-biphenyl-4-yl)-methanol(compound 3A)

1-Bromo-4-trifluoromethyl-benzene (814 mg, 3.62 mmol),4-hydroxymethylphenylboronic acid (600 mg, 3.98 mmol), cesium carbonate(2.36 g, 7.24 mmol), and PdCl₂(dppf) (132 mg, 0.181 mmol) were added to10 ml of a 1:1 solution of DMF/THF. The reaction was flushed withnitrogen and heated to 90° C. for 1 h. The reaction was cooled, pouredinto diethyl ether and washed with water (2×50 ml), brine (1×50 ml) anddried over anhydrous sodium sulfate. The crude product was filteredthrough silica gel, eluted: with diethyl ether, and concentrated toprovide the title compound. MS m/z 251 (M−1).Step 2. Preparation of 4-Chloromethyl-4′-trifluoromethyl-biphenyl(compound 3B)

The product from Example 3A was dissolved in 10 ml methylene chloride.Triethylamine (468 mg, 4.62 mol) and methanesulfonyl chloride (422 mg,3.68 mmol) were then added and stirred for 18 h. The reaction was pouredinto water and extracted with methylene chloride. The organic solutionwas dried over anhydrous sodium sulfate, decanted and concentrated toprovide the title compound that was used without further purification.MS m/z 235 (M-Cl+1).Step 3. Preparation of[2-Methyl-4(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid methyl ester (compound 3C)

The title compound was prepared in the manner analogous to Example 1Fusing 3B and 2C. MS m/z 447 (M+1).Step 4. Preparation of[2-Methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 3)The title compound was prepared in the manner analogous to Example 1using 3C. mp 140-141° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 12.95 (br(s), 1H),7.82 (d, 2H, J=8.4 Hz), 7.74 (d, 2H, J=8.4 Hz), 7.61 (d, 2H, J=8.4 Hz),7.35 (d, 2H, J=8.4 Hz), 7.10 (m, 2H), 6.70 (d, 1H, J=8.4 Hz), 4.62 (s,2H), 4.13 (s, 2H), 2.08 (s, 3H); MS m/z 431 (M−1). Anal. Calc'd forC₂₃H₁₉F₃O₃S.0.7 H₂O C, 62.07; H, 4.62; found: C, 61.98; H, 4.22.

EXAMPLE 4

Synthesis of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 4)

Step 1. Preparation of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid methyl ester (compound 4A)

The title compound was prepared in the manner analogous to Example 1Fusing 1D and 3B. MS m/z 477 (M+1).Step 2. Preparation of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 4)The title compound was prepared in the manner analogous to Example 1using 4A. mp 170-171° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 7.81 (d, 2H, J=8Hz), 7.60 (d, 2H, J 8.4 Hz), 7.32 (d, 2H, J=8.4 Hz), 7.02 (s, 1H), 6.52(s, 1H), 4.70 (s, 2H), 4.03 (s, 2H), 3.73 (s, 3H), 2.00 (s, 3H). MS m/z463 (M+1). Anal. Calc'd for C₂₄H₂₁F₃NO₄S.0.1 H₂O C, 62.09; H, 4.60;found: C, 62.00; H, 4.36.

EXAMPLE 5

Synthesis of[5-Methoxy-2-methyl-4-(2′,4′,6′-trimethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 5)

Step 1. Preparation of[5-Methoxy-2-methyl-4-(2′,4′,6′-trimethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid methyl ester (compound 5A)

2-Bromo-1,3,5-trimethyl-benzene (396 mg, 2mmol),4-hydroxymethylphenylboronic acid (334 mg, 2.2 mmol), cesium carbonate(1.3 g, 4 mmol), and PdCl₂(dppf) (82 mg, 0.1 mmol) were added to 5 ml ofa 1:1 solution of DMF/THF. The reaction was flushed with nitrogen andheated to 90° C. for 1 h. The reaction was cooled, poured into diethylether and washed with water (2×10 ml), brine (1×10 ml) and dried overanhydrous sodium sulfate. The organic solution was filtered throughsilica gel, eluted with diethyl ether, and concentrated. The crudeproduct was dissolved in 10 ml dichloromethane. Added to this solutionwere triethylamine (202 mg, 2 mmol) then methanesulfonyl chloride (184mg, 1.6 mmol) and allowed to stir at ambient temperature for 18 h. Thereaction was poured into water and extracted with methylene chloride.The organic solution was dried over anhydrous sodium sulfate, decantedand concentrated to provide the crude alkyl chloride. The product fromExample 1D (387 mg, 1.6 mmol), the crude4′-chloromethyl-2,4,6-trimethyl-biphenyl, and cesium carbonate (1 g,3.06 mmol) were stirred in 10 ml acetonitrile for 3 h, filtered,concentrated, and purified by normal phase chromatography to afford thetitle product. MS m/z 451 (M+1).Step 2. Preparation of[5-Methoxy-2-methyl-4-(2′,4′,6′-trimethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacidThe title compound was prepared in the manner analogous to Example 1using 5A. mp 141° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 12.81 (br(s), 1H), 7.04(d, 2H, J=8.4 Hz), 6.77 (m, 3H), 6.69 (s, 2H), 6.36 (s, 1H), 4.43 (s,2H), 3.82 (s, 2H), 3.58 (s, 3H), 2.03 (s, 3H), 1.82 (s, 3H), 1.67 (s,6H). MS m/z 437 (M+1).

EXAMPLE 6

Synthesis of[4-(4′-Chloro-3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-2-methyl-phenoxy]-aceticacid (compound 6)

Step 1. Preparation of(4′-Chloro-3′-trifluoromethyl-biphenyl-4-yl)-methanol (compound 6A)

The title compound was prepared in the manner analogous to Example 3Ausing 4-bromo-1-chloro-2-trifluoromethyl-benzene. MS m/z 288 (M+1).

-   -   Step 2. Preparation of        4-Chloro-4′-chloromethyl-3′-trifluoromethyl-biphenyl (compound        6B)        The title compound was prepared in the manner analogous to        Example 3B using 6A. MS m/z 305 (M).        Step 3. Preparation of        [4-(4′-Chloro-3′-trifluoromethyl-biphenyl-4ylmethylsulfanyl)-2-methyl-phenoxy]-acetic        acid methyl ester (compound 6C)        The title compound was prepared in the manner analogous to        Example 1F using 2C and 6B. MS m/z 481 (M+1).        Step 4. Preparation of        [4-(4′-Chloro-3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-2-methyl-phenoxy]-acetic        acid (compound 6)        The title compound was prepared in the manner analogous to        Example 1 using 6C. 400 MHz ¹H NMR (DMSO-d₆) δ 7.97 (s, 1H),        7.92 (d, 1H, J=10.5 Hz), 7.74 (d, 1H, J=10.5 Hz), 7.64 (d, 2H,        J=8.9 Hz), 7.34 (d, 2H, J=8.9 Hz), 7.14 (s, 1H), 7.08 (d, 1H,        J=11.0 Hz), 6.70 (d, 1H, J=11.0 Hz), 4.62 (s, 2H), 4.12 (s, 2H),        2.08 (s, 3H); MS m/z 465 (M−1).

EXAMPLE 7

Synthesis of[4-(2′,4′-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxyl-aceticacid (compound 7)

Step 1. Preparation of[4(2′,4′-Dichloro-biphenyl-4ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid methyl ester (compound 7A)

The title compound was prepared in the manner analogous to Example 5Ausing 1D and 1-bromo-2,4-dichloro-benzene. MS m/z 479 (M+2).Step 2. Preparation of[4-(2′,4′-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid (compound 7)The title compound was prepared in the manner analogous to Example 1using 7A. 400 MHz ¹H NMR (DMSO-d₆) δ 12.95 (br(s, 1H), 7.67 (dd, 1H,J′=2 Hz, J=8.4 Hz), 7.43 (d, 1H, J=2.4 Hz), 7.37 (s, 1H), 7.28 (s, 4H),7.02 (s, 1H), 6.52 (s, 1H), 4.70 (s, 2H), 4.02 (s, 2H), 3.72 (s, 3H),2.01 (s, 3H); MS m/z 465 (M+2).

EXAMPLE 8

Synthesis of[4-(3′,4′-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid (compound 8)

Step 1. Preparation of[4-(3′,4′-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid methyl ester (compound 8A)

The title compound was prepared in the manner analogous to Example 5Ausing 1D and 4-bromo-1,2-dichlorobenzene. MS m/z 479 (M+2).Step 2. Preparation of[4-(3′,4′-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid (compound 8)The title compound was prepared in the manner analogous to Example 1using 8A. mp 161-162° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 7.87 (d, 1H, J=2Hz), 7.57-7.66 (m, 4H), 7.29 (d, 2H, J=8.4 Hz), 7.01 (s, 1H), 6.52 (s,1H), 4.69 (s, 2H), 4.02 (s, 2H), 3.72 (s, 3H), 2.03 (s, 3H); MS m/z 494(M+1).

EXAMPLE 9

Synthesis of[5-Methoxy-2-methyl-4-(3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 9)

Step 1. Preparation of[5-Methoxy-2-methyl-4-(3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid methyl ester (compound 9A)

The title compound was prepared in the manner analogous to Example 5Ausing 1D and 1-bromo-3-trifluoromethyl-benzene. MS m/z 477 (M+1).Step 2. Preparation of[5-Methoxy-2-methyl-4-(3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 9)The title compound was prepared in the manner analogous to Example 1using 9A. mp 138-139° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 12.95 (br(s), 1H),7.91 (m, 2), 7.63 (m, 4H), 7.32 (d, 2H, J=8.4 Hz), 7.02 (s, 1H), 6.52(s, 1H), 4.69 (s, 2H), 4.03 (s, 2H), 3.73 (s, 3H), 2.06 (s, 3H); MS m/z463 (M+1).

EXAMPLE 10

Synthesis of[4-(4′-Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid (compound 10)

Step 1. Preparation of (4′-Fluoro-biphenyl-4-yl)-methanol (compound 10A)

The title compound was prepared in the manner analogous to Example 3Ausing 1-bromo-4-fluorobenzene. MS m/z 185 (M-H₂O).Step 2. Preparation of 4-Chloromethyl-4′-fluoro-biphenyl (compound 10B).

EXAMPLE 10B

The title compound was prepared in the manner analogous to Example 3Busing 10A. MS m/z 222 (M+2).

Step 3. Preparation of[4(4′-Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid methyl ester (compound 10C)

The title compound was prepared in the manner analogous to Example 1Fusing 10B and 1D. MS m/z 427 (M+1).

Step 4. Preparation of[4-(4′-Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid

The title compound was prepared in the manner analogous to Example 1using 10C. 400 MHz ¹H NMR (DMSO-d₆) δ 12.93 (br(s), 1H), 7.62 (m, 2H),7.49 (d, 2H, J=8.4 Hz), 7.27 (d, 2H, J=8.4 Hz), 7.22 (m, 2H), 7.02 (s,1H), 6.52 (s, 1H), 4.69 (s, 2H), 4.01 (s, 2H), 3.73 (s, 3H), 2.01 (s,3H). MS m/z 411 (M−1).

EXAMPLE 11

Synthesis of[5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 11)

Step 1. Preparation of[5-Methoxy-2-methyl-4(3′-trifluoromethoxy-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid methyl ester (compound 11A)

The title compound was prepared in the manner analogous to Example 5Ausing 1D and 1-bromo-3-trifluoromethoxy-benzene. MS m/z 493 (M+1).Step 2. Preparation of[5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 11)The title compound was prepared in the manner analogous to Example 1using 11A. mp 137° C.; 400 m/z ¹H NMR (DMSO-d₆) δ 12.95 (br(s), 1H),7.66 (d, 1H, J=8.8 Hz), 7.56 (m, 4H), 7.30 (m, 3H), 7.02 (s, 1H), 6.52(s, 1H), 4.69 (s, 2H), 4.02 (s, 2H), 3.73 (s, 3H), 2.01 (s, 3H). MS m/z493 (M+1).

EXAMPLE 12

Synthesis of[7-(4′-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid (compound 12)

Step 1. Preparation of Indan-4-ol (compound 12A)

A mixture of 4-hydroxy-indan-1-one (5.0 g, 33.7 mmol), sodiumcyanoborohydride (6.4 g, 101.1 mmol), and zinc iodide (32.3 g, 101.1mmol) in dichloromethane, was heated at reflux for two hours. Thereaction mixture was then filtered through 50 g SiO₂ while still warm,eluting further with dichloroethane. The filtrate was collected andconcentrated under vacuum. The residue was added to diethyl ether andthe resulting white precipitate was filtered off. The filtrate wascollected and concentrated in vacuo to give 4.2 g of the title, compoundwith purity high enough for subsequent use. 400 MHz ¹H NMR (DMSO-d₆) δ9.06 (s, 1H), 6.86 (t, 1H, J=7.8 Hz), 6.59 (d, 1H, J=7.8 Hz), 6.48 (d,1H, J=7.8 Hz), 2.75 (t, 2H, J=7.3 Hz), 2.67 (t, 2H, J=7.3 Hz), 1.92 (m,2H).Step 2. Preparation of 7-Thiocyanato-indan-4-ol (compound 12B)

The title compound was prepared in the manner analogous to Example 1Busing 12A. MS m/z 192 (M+1).Step 3. Preparation of (7-Mercapto-indan-4-yloxy)-acetic acid methylester (compound 12C)

7-Thiocyanato-indan-4ol (Example 12B) (1.47 g, 7.7 mmol), cesiumcarbonate (3.77 g, 11.6 mmol) and methyl bromoacetate (1.24 g, 8.08mmol) were stirred in 20 ml acetonitrile at ambient temperature for 4 h.The reaction was filtered and concentrated. The crude product wastreated under the conditions of Example 1D to afford the title product.MS m/z 239 (M+1).Step 4. Preparation of[7-(4′-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid methyl ester (compound 12D)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 3B. MS m/z 473 (M+1).Step 5. Preparation17-(4′-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid (compound 12)The title compound was prepared in the manner analogous to Example 1using 12D. mp 158-159° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 12.94 (br(s), 1H),7.82 (d, 2H, J=8 Hz), 7.74 (d, 2H, J=8.8 Hz), 7.60 (d, 2H, J=6.4 Hz),7.31 (d, 2H, J=8 Hz), 7.08 (d, 1H, J=8.8 Hz), 6.58 (d, 1H, J=8.4 Hz),4.61 (s, 2H), 4.06 (s, 2H), 2.72 (m, 4H), 1.90 (q, 2H); MS m/z 457(M−1).

EXAMPLE 13

Synthesis of [4-(4-Benzyloxy-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid (compound 13)

Step 1. Preparation of[4-(4-Benzyloxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid methylester (compound 13A)

The title compound was prepared in the manner analogous to Example 1Fusing 1-chloromethyl-4-benzyloxy-benzene and 2C. MS m/z 409 (M+1).Step 2. Preparation of[4-(4-Benzyloxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid (compound13)The title compound was prepared in the manner analogous to Example 1 and13A. mp 120-121° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 7.39-7.25 (m, 5H),7.15-7.03 (m, 4), 6.85 (d, 2H, J=8.5 Hz), 6.68 (d, 1H, J 8.4 Hz), 5.00(s, 2H), 4.62 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H); MS m/z 395 (M+1).

EXAMPLE 14

Synthesis of{5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid (compound 14)

Step 1. Preparation of [4-(4-Trifluoromethyl-benzyloxy)-phenyl]-methanol(compound 14A)

4-Hydroxymethyl-phenol (1 g, 8.06 mmol),1-Chloromethyl-4-trifluoromethyl-benzene (1.57 g, 8.06 mmol), and cesiumcarbonate (5.26 g, 16.12 mmol) were refluxed in acetonitrile for 20 h,cooled, filtered, and concentrated to give the title compound. MS m/z265 (M-H₂O+1).Step 2. Preparation of4-Chloromethyl-(4-trifluoromethyl-benzyloxy-benzene) (compound 14B)

The title compound was prepared in the manner analogous to Example 3Busing 14A. MS m/z 265 (M-Cl+1).Step 3. Preparation of{5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 14C)

The title compound was prepared in the manner analogous to Example 1Fusing 14B and 1D. MS m/z 507 (M+1).Step 4. Preparation of{5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid (compound 14)The title compound was prepared in the manner analogous to Example 1using 14C. mp 145° C. 400 MHz ¹H NMR (DMSO-d₆) δ 12.94 (br(s), 1H), 7.70(d, 2H, J=8 Hz), 7.76 (d, 2H, J=8 Hz), 7.14 (d, 2H, J=8.8 Hz), 6.97 (s,1H), 6.87 (m, 2H), 6.50 (s, 1H), 5.14 (s, 2H), 4.68 (s, 2H), 3.91 (s,2H), 3.71 (s, 3H), 2.00 (s, 3H); MS m/z 491 (M−1).

EXAMPLE 15

Synthesis of{2-Methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid (compound 15)

Step 1. Preparation of{2-Methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 15A)

The title compound was prepared in the manner analogous to Example 1Fusing 2C and 14B. MS m/z 477 (M+1).Step 2. Preparation of{2-Methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid (compound 15)The title compound was prepared in the manner analogous to Example 1using 15A. mp 133° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 7.70 (d, 2H, J=8 Hz),7.76 (d, 2H, J=8 Hz), 7.14 (d, 2H, J=8.8 Hz), 7.09 (m, 1H), 7.04 (dd,1H, J=2.4 Hz, J′=8.4 Hz), 6.87 (m, 2H), 6.68 (d, 1H, J=8.4 Hz), 5.14 (s,2H), 4.61 (s, 2H), 3.99 (s, 2H), 2.08 (s, 3H); MS m/z 461 (M−1).

EXAMPLE 16

Synthesis of[5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 16)

Step 1. Preparation of (3′-Trifluoromethoxy-biphenyl-3-yl)-methanol(compound 16A)

The title compound was prepared in the manner analogous to Example 3Ausing 3-hydroxymethylphenylboronic acid and1-bromo-3-trifluoromethoxy-benzene. MS m/z 251 (M−1).Step 2. Preparation of 3-Chloromethyl-3′-trifluoromethoxy-biphenyl(compound 16B)

The title compound was prepared in the manner analogous to Example 3Busing 16A. MS m/z 251 (M−1).Step 2. Preparation of[5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid methyl ester (compound 16C)

The title compound was prepared in the manner analogous to Example 1Fusing 16B and 1D. MS m/z 491 (M−1).Step 4. Preparation of[5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 16)The title compound was prepared in the manner analogous to Example 1using 16C. mp 92-94° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 12.96 (br(s), 1H),7.55-7.24 (m, 8H), 7.01 (s, 1H), 6.52 (s, 1H), 4.68 (s, 2H), 4.03 (s,2H), 3.72 (s, 3H), 1.99 (s, 3H); MS m/z 479 (M+1).

EXAMPLE 17

Synthesis of [4-(9H-Fluoren-2-ylmethylsulfanyl-2-methyl-phenoxy]-aceticacid (compound 17)

Step 1. Preparation of (9H-Fluoren-2-yl)-methanol (compound 17A)

9H-Fluorene-2-carbaldehyde (500 mg, 2.6 mmol) was dissolved in 10 mlmethanol. Sodium borohydride (200 mg, 5.2 mmol) was added and allowed tostir at ambient temperature for 1 h. Water (10 ml) was added and thecrude product was extracted into ethyl acetate (50 ml), washed withbrine (50 ml), dried over anhydrous sodium sulfate, decanted andconcentrated to afford the title product in good purity. MS m/z 195(M+1).Step 2. Preparation of 2-Chloromethyl-9H-fluorene (compound 17B)

The title compound was prepared in the manner analogous to Example 3Busing 17A. MS m/z 179 (M-Cl+1).Step 3. Preparation of[4-(9H-Fluoren-2-ylmethylsulfanyl-2-methyl-phenoxy]-acetic acid methylester (compound 17C)

The title compound was prepared in the manner analogous to Example 1Fusing 17B and 2C. MS m/z 422 (M+1).Step 4. Preparation of[4-(9H-Fluoren-2-ylmethylsulfanyl-2-methyl-phenoxy]-acetic acid(compound 17)The title compound was prepared in the manner analogous to Example 1using 17C. 400 MHz ¹H NMR (DMSO-d₆) δ 12.93 (br(s), 1H), 7.80 (d, 1H,J=7.6 Hz), 7.23 (d, 1H, J=8 Hz), 7.5 (d, 1H, J=7.6 Hz), 7.43 (s, 1H),7.31 (t, 1H, J′=6.4 Hz), 7.24 (m, 2H), 7.15 (m, 1H), 7.08 (dd, 1H, J=2.4Hz, J=8.4 Hz), 6.7 (d, 1H, J=8.8 Hz), 4.62 (s, 2H), 4.13 (s, 2H), 3.82(s, 2H), 2.09 (s, 3H). MS m/z 375 (M−1). Anal. Calc'd for C₂₃H₂₀O₃S.0.3H₂O C, 72.34; H, 5.44; found: C, 72.46; H, 5.20.

EXAMPLE 18

Synthesis of{{5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid (compound 18)

Preparation of [4-(5-Trifluoromethyl-pyridin-2-yl)-phenyl]-methanol(compound 18A)

The title compound was prepared from 2-Chloro-5-trifluoromethyl-pyridineand 4-(hydroxymethyl)boronic acid PdCl₂(dppb) catalyst in the manneranalogous to Example 3A. 400 MHz ¹H NMR (DMSO-d₆) δ 8.98 (s, 1H), 8.2(dd, 1H, J=2.4 Hz, J′=8.4 Hz), 8.09 (m, 3H), 7.42 (d, 2H, J=8.54 Hz),5.23 (t, 1H), 4.54 (d, 2H, J=6 Hz); MS m/z 254 (M+1).Preparation of 2-(4-Chloromethyl-phenyl) 5-trifluoromethyl-pyridine(compound 18B)

The title compound was prepared in the manner analogous to Example 3Busing 18A. MS m/z 272 (M+1).Preparation of{5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 18C)

The title compound was prepared in the manner analogous to Example 1Fusing 1D and 18B. MS m/z 478 (M+1).Preparation of{5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid (compound 18)The title compound was prepared from the product of Example 18C in themanner analogous to Example 1. mp 225° C. (dec.); 400 MHz ¹H NMR(DMSO-d₆) δ 8.97 (s, 1H), 8.2 (dd, 1H, J=2.4 Hz, J′=8.4 Hz), 8.13 (m,1H), 8.01 (d, 2H, J=8.4 Hz), 7.34 (s, 2H, J=8.4 Hz), 6.95 (s, 1H), 6.42(s, 1H), 4.23 (s, 2H), 4.01 (s, 2H), 3.69 (s, 3H), 1.96 (s, 3H) MS m/z464 (M+1).

EXAMPLE 19

Synthesis of45-Methoxy-2-methyl-4-[6-(4-trifluoromethylphenyl)-pyridin-3-ylmethylsulfanyl]-phenoxy}-aceticacid (compound 19)

Step 1. Preparation of[4-(6-Chloro-pyridin-3-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid methyl ester (compound 19A)

The title compound was prepared from 2-Chloro-5-chloromethyl-pyridineand 1D in a manner analogous to Example 1F. MS m/z 370 (M+2).Step 2. Preparation of{5-Methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 19B)

The title compound was prepared from the product of Example 19A and1-bromo-4-trifluoromethyl-benzene in a manner analogous to Example 3A.MS m/z 478 (M+1).Step 3. Preparation of{5-Methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethylsulfanyl]-phenoxy}-aceticacid (compound 19)The title compound was prepared from the product of Example 19B in themanner analogous to Example 1. mp 203° C. (dec.); 400 MHz ¹H NMR(DMSO-d₆) δ 8.34 (d, 1H, J=1.6 Hz), 8.21 (d, 2H, J=8 Hz), 7.92 (d, 1H,J=8.4 Hz), 7.77 (d, 2H, J=8.4 Hz), 7.65 (dd, 1H, J′=2.4 Hz, J=8.4 Hz),6.93 (s, 1H), 6.39 (s, 1H), 4.15 (s, 2H), 4.00 (s, 2H), 3.66 (s, 3H),1.95 (s, 3H). MS m/z 464 (M+1).

EXAMPLE 20

Synthesis of[5-Chloro-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 20)

Step 1. Preparation of 5-Chloro-2-methyl-4-thiocyanato-phenol (compound20A)

The title compound was prepared in a manner analogous to Example 1B from5-chloro-2-methyl-phenol. 400 MHz ¹H NMR (DMSO-d₆) δ 10.60 (s, 1H), 7.54(s, 1H), 6.98 (s, 1H), 2.07 (s, 3H).Step 2. Preparation of (5-Chloro-2-methyl-4-thiocyanato-phenoxy)-aceticacid methyl ester(compound 20B)

The title compound was prepared from the product of Example 20A in amanner analogous to Example 1C. 400 MHz ¹H NMR (DMSO-d₆) δ 7.62 (s, 1H),7.40 (s, 1H), 4.94 (s, 2H), 3.65 (s, 3H), 2.15 (s, 3H).Step 3. Preparation of (5-Chloro-4-mercapto-2-methyl-phenoxy)-aceticacid methyl ester (compound 20C)

The title compound was prepared from(5-chloro-2-methyl-4-thiocyanato-phenoxy)-acetic acid methyl ester in amanner analogous to Example 1D. 400 MHz ¹H NMR (DMSO-d₆) δ 7.27 (s, 1H),6.97 (s, 1H), 5.31 (s, 1H), 4.79 (s, 2H), 3.64 (s, 3H), 2.07 (s, 3H).Step 4. Preparation of[5-Chloro-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)phenoxy]-aceticacid methyl ester (compound 20D)

The title compound was prepared in the manner analogous to Example 1Fusing 3B and 20C. 400 MHz ¹H NMR (DMSO-d₆) δ 7.82 (d, 2H, J=8.3 Hz),7.74 (d, 2H, J=8.3 Hz), 7.62 (d, 2H, J=8.3 Hz), 7.39 (d, 2H, J=8.3 Hz),7.27 (s, 1H), 7.00 (s, 1H), 4.82 (s, 2H), 4.20 (s, 2H), 3.64 (s, 3H),2.09 (s, 3H); MS m/z 480 (M+).Step 5. Preparation of[5-Chloro-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 20)

The title compound was prepared in the manner analogous to Example 1using 20D. mp 161-162° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 7.83 (d, 2H, J=8.3Hz), 7.74 (d, 2H, J=8.3 Hz), 7.62 (d, 2H, J=8.3 Hz), 7.51 (d, 2H, J=8.3Hz), 7.26 (s, 1H), 6.95 (s, 1H), 4.69 (s, 2H), 4.20 (s, 2H), 2.08 (s,3H); MS m/z 467 (M+1).

EXAMPLE 21

Synthesis of[3-Methoxy-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 21)

Step 1. Preparation of 3-Methoxy-4-thiocyanato-phenol (compound 21A)

The title compound was prepared in a manner analogous to Example 1B from3-methoxy-phenol. 400 MHz ¹H NMR (DMSO-d₆) δ 10.21 (s, 1H), 7.34 (d, 1H,J=8.3 Hz), 6.53 (s, 1H), 6.43 (d, 1H, J=8.3 Hz), 3.81 (s, 3H).Step 2. Preparation of (3-Methoxy-4-thiocyanato-phenoxy)-acetic acidmethyl ester (compound 21B)

The title compound was prepared from the product of Example 21A in amanner analogous to Example 1C. MS m/z 227 (M-CN).Step 4. Preparation of (4-Mercapto-3-methoxy-phenoxy)-acetic acid methylester (compound 21C)

The title compound was prepared from(3-Methoxy-4-thiocyanato-phenoxy)-acetic acid methyl ester in a manneranalogous to Example 1D. 400 MHz ¹H NMR (DMSO-d₆) δ 7.13 (d, 1H, J=8.5Hz), 6.56 (s, 1H), 6.39 (d, 1H, J=8.5 Hz), 4.72 (s, 2H), 4.51 (s, 1H),3.75 (s, 3H), 3.64 (s, 3H).Step 5. Preparation of[3-Methoxy-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid methyl ester (compound 21D)

The title compound was prepared in the manner analogous to Example 1Fusing 3B and 21C. 400 MHz ¹H NMR (DMSO-d₆) δ 7.81 (d, 2H, J=8.3 Hz),7.53 (d, 2H, J=8.3 Hz), 7.59 (d, 2H, J=8.3 Hz), 7.32 (d, 2H, J=8.3 Hz),7.11 (d, 1H, J=8.5 Hz), 6.56 (s, 1H), 6.37 (d, 1H, J=8.5 Hz), 4.73 (s,2H), 4.04 (s, 2H), 3.76 (s, 3H), 3.63 (s, 3H); MS m/z 463 (M+1).Step 6. Preparation of[3-Methoxy-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 21)

The title compound was prepared in the manner analogous to Example 1using 21D. 400 MHz ¹H NMR (DMSO-d₆) δ 7.83 (d, 2H, J=8.3 Hz), 7.76 (d,2H, J=8.3 Hz), 7.61 (d, 2H, J=8.3 Hz), 7.34 (d, 2H, J=8.3 Hz), 7.13 (d,1H, J=8.5 Hz), 6.56 (s, 1H), 6.39 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 4.06(s, 2H), 3.77 (s, 3H); MS m/z 449 (M+1). Anal. Calc'd for C₂₃H₁₉F₃O₄S,C, 61.60; H, 4.27; found: C, 61.35; H, 4.25.

EXAMPLE 22

Synthesis of{2-Methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}-aceticacid (compound 22)

Step 1. Preparation of 2-(4′-Trifluoromethyl-biphenyl-4-yl)-ethanol(compound 22A)

A mixture of 2-(4-bromo-phenyl)-ethanol (2.3 ml, 3.3 g, 16.4 mmol),4-trifluoromethylphenylboronic acid (5.0 g, 26.3 mmol), 1.0 M aqueoussodium carbonate solution (44.0 ml), andtetrakis(triphenylphosphine)palladium (0.98 g, 0.85 mmol) in 180 ml ofethanol and 180 ml of toluene was heated at reflux for 4 h. The cooledreaction mixture was diluted with 500 ml of ethyl acetate and filteredthrough a bed of Celite filter-aid. The filtrate was washed with 5%aqueous sodium carbonate solution (2×750 ml) and brine (3×750 ml), thendried over anhydrous sodium sulfate and concentrated. The crude productwas purified by normal phase chromatography. MS m/z 266 (M).Step 2. Preparation of 4-(2-Bromo-ethyl)-4′-trifluoromethyl-biphenyl(compound 22B)

A solution of 2-(4′-trifluoromethyl-biphenyl-4-yl)-ethanol (2.8 g, 10.3mmol) and carbon tetrabromide (3.8 g, 11.5 mmol) in 50 ml ofdichloromethane was cooled in ice, and triphenylphosphine (2.9 g, 11.1mmol) was added in portions over 10 minutes. The mixture was stirred atroom temperature for 18 h, and the solvent was evaporated. The residuewas stirred in 75 ml of ether, and the mixture was filtered. Theinsoluble material was washed on the funnel with fresh ether (3×75 ml).The combined ether filtrates were concentrated, and the crude productwas purified by normal phase chromatography. MS m/z 328 (M−1).Step 3. Preparation of{2-Methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 22C)

A solution 4-(2-bromo-ethyl)-4′-trifluoromethyl-biphenyl (0.66 g, 2.0mmol) and (4-mercapto-2-methyl-phenoxy)-acetic acid methyl ester (0.42g, 2.0 mmol) in 10 ml of acetonitrile was treated with cesium carbonate(1.3 g, 4.0 mmol), and the mixture was stirred at room temperature for18 h. The reaction mixture was added to 200 ml of brine and extractedwith ethyl acetate (4×75 ml). The combined extracts were washed withbrine (2×200 ml), then dried over anhydrous sodium sulfate andconcentrated. The crude product was purified by normal phasechromatography. MS m/z 461 (M+1).Step 4. Preparation of{2-Methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}aceticacid (compound 22)A solution of{2-methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}-aceticacid methyl ester (0.78 g, 1.7 mmol) in 10 ml of tetrahydrofuran and 2.0ml of water was treated with lithium hydroxide monohydrate (0.21 g, 5.0mmol), and the mixture was stirred at room temperature for 2 h. Thereaction mixture was diluted with 5.0 ml of water and made stronglyacidic by the addition of 4.0 N hydrochloric acid. The mixture wasextracted with ethyl acetate (4×30 ml), and the combined extracts werewashed with brine (2×50 ml), then dried over anhydrous sodium sulfateand concentrated. The crude product was recrystallized from ethylacetate/hexane. mp 132-134° C. IR (thin film) cm⁻¹: 1741, 1709, 1490,1326, 1239, 1110; 400 MHz ¹H NMR (DMSO-d₆) δ 7.82 (d, 2H, J=8.0 Hz),7.74 (d, 2H, J=8.0 Hz), 7.61 (d, 2H, J=8.3 Hz), 7.31 (d, 2H, J=8.3 Hz),7.15 (m, 2H), 6.75 (d, 1H, J=8.3 Hz), 4.64 (s, 2H), 3.11 (t, 2H, J=7.6Hz), 2.82 (t, 2H, J=7.6 Hz), 2.12 (s, 3H); MS m/z 447 (M+1). Anal.Calc'd for C₂₄H₂₁F₃O₃S: C, 64.56; H, 4.74; found: C, 64.45; H, 4.58.

EXAMPLE 23

Synthesis of{5-Methoxy-2-methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}-aceticacid (compound 23)

Step 1. Preparation of{5-Methoxy-2-methyl-4-[2-(4-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 23A)

The title compound was prepared in the manner analogous to Example 22Cusing 4-(2-bromo-ethyl)-4′-trifluoromethyl-biphenyl and 1D. MS m/z 491(M+1).Step 2. Preparation of{5-Methoxy-2-methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}-aceticacid (compound 23)The title compound was prepared in the manner analogous to Example 1using{5-methoxy-2-methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}-aceticacid methyl ester. mp 169-171° C.; IR (thin film) cm⁻¹: 1718, 1500,1330, 1162, 1109, 1052; 400 MHz ¹H NMR (DMSO-d₆) δ 7.82 (d, 2H, J=8.3Hz), 7.74 (d, 2H, J=8.6 Hz), 7.61 (d, 2H, J=8.3 Hz), 7.31 (d, 2H, J=8.3Hz), 7.06 (s, 1H), 6.53 (s, 1H), 4.69 (s, 2H), 3.73 (s, 3H), 3.02 (t,2H, J=7.5 Hz), 2.78 (t, 2H, J=7.5 Hz), 2.06 (s, 3H); MS m/z 477 (M+1).Anal. Calc'd for C₂₅H₂₃F₃O₄S: C, 63.02; H, 4.87; found: C, 62.77; H,4.62.

EXAMPLE 24

Synthesis of{2-Methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-vinyl]-phenoxy}-aceticacid (compound 24)

Step 1. Preparation of (4-Bromo-2-methyl-phenoxy)-acetic acid methylester (compound 24A)

A solution of o-tolyloxy-acetic acid methyl ester (Belleney J., et al.,J. Heterocyclic Chem., 1984; 21:1431; 3.7 g, 20.5 mmol) in 70 ml ofacetonitrile was treated in portions over 10 minutes withN-bromosuccinimide (3.8 g, 21.3 mmol). The mixture was stirred at roomtemperature for 18 h, and the solvent was evaporated. The residue wasstirred in 75 ml of carbon tetrachloride, and the mixture was filtered.The insoluble material was washed on the funnel with fresh carbontetrachloride (2×50 ml). The combined filtrates were concentrated, andthe crude product was purified by normal phase chromatography. MS m/z258 (M−1).Step 2. Preparation of 4-Trifluoromethyl-4′-vinyl-biphenyl (compound24B)

The title compound was prepared in the manner analogous to Example 3Ausing 1-bromo-4-vinyl-benzene and 4-trifluoromethylphenylboronic acid.MS m/z 248 (M).Step 3. Preparation of{2-Methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-vinyl]-phenoxy}-aceticacid methyl ester and{2-methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-vinyl]-phenoxy}-aceticacid (compound 24)A mixture of 4-trifluoromethyl-4′-vinyl-biphenyl (1.9 g, 7.7 mmol),(4-Bromo-2-methyl-phenoxy)-acetic acid methyl ester (2.0 g, 7.7 mmol),anhydrous sodium acetate (1.2 g, 14.6 mmol), N,N-dimethylglycine (0.23g, 2.2 mmol), and palladium acetate (0.025 g, 0.11 mmol) in 10 ml of1-methyl-pyrrolidin-2-one was heated at 130° C. for 10 h. The reactionmixture was partitioned between 250 ml of brine and 300 ml of ethylacetate. The total mixture was filtered through a bed of Celitefilter-aid. The organic layer was washed with 5% aqueous sodiumcarbonate solution (3×250 ml) and brine (2×250 ml), then dried overanhydrous sodium sulfate and concentrated. The residue was purified bynormal phase chromatography to give{2-methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-vinyl]-phenoxy}-aceticacid methyl ester; MS m/z 427 (M+1).

During the above sodium carbonate washings, a precipitate formed and wasremoved by filtration. The solid was stirred for 18 h in a solution of150 ml of water, 50 ml of methanol, and 50 ml of 4.0 N hydrochloricacid. The acidified product was filtered and recrystallized from aqueousacetonitrile to give{2-methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-vinyl]-phenoxy}-aceticacid. mp 243-245° C.; IR (thin film) cm⁻¹: 1746, 1717, 1502, 1323, 1125,1069; 400 MHz ¹H NMR (DMSO-d₆) δ 7.88 (d, 2H, J=8.0 Hz), 7.76 (d, 2H,J=8.3 Hz), 7.71 (d, 2H, J=8.5 Hz), 7.64 (d, 2H, J=8.5 Hz), 7.43 (d, 1H,J=1.7 Hz), 7.32 (dd, 1H, J=2.1, 8.5 Hz), 7.21 (d, 1H, J=16.5 Hz), 7.10(d, 1H, J=16.4 Hz), 6.79 (d, 1H, J=8.5 Hz), 4.68 (s, 2H), 2.18 (s, 3H);MS m/z 413 (M+1). Anal. Calc'd for C₂₄H₁₉F₃O₃: C, 69.90; H, 4.64; found:C, 69.77; H, 4.57.

EXAMPLE 25

Synthesis of{2-Methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-ethyl]-phenoxy}-aceticacid (compound 25)

A solution of{2-methyl-4-[2-4′-trifluoromethyl-biphenyl-4-yl)-vinyl]-phenoxy}-aceticacid (0.98 g, 2.4 mmol) in 100 ml of tetrahydrofuran was hydrogenatedover 0.16 g of 20% palladium on carbon catalyst. The catalyst wasremoved by filtration, and the filtrate was evaporated. The crudeproduct was recrystallized from aqueous acetonitrile. mp 174-176° C.; IR(thin film) cm⁻¹: 1747, 1711, 1500, 1318, 1160, 1123; 400 MHz ¹H NMR(DMSO-d₆) δ 7.83 (d, 2H, J=8.1 Hz), 7.74 (d, 2H, J=8.3 Hz), 7.60 (d, 2H,J=6.5 Hz), 7.32 (d, 2H, J=8.3 Hz), 7.01 (d, 1H, J=2.0 Hz), 6.94 (dd, 1H,J=2.0, 8.3 Hz), 6.66 (d, 1H, J=8.3 Hz), 4.59 (s, 2H), 2.83 (m, 2H), 2.76(m, 2H), 2.11 (s, 3H); MS m/z 413 (M−1). Anal. Calc'd for C₂₄H₂₁F₃O₃: C,69.56; H, 5.11; found: C, 69.28; H, 4.96.

EXAMPLE 26

Synthesis of{7-[4-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 26)

Step 1. Preparation of{7-[4-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 26A)

The title compound was prepared in the manner analogous to Example 1Fusing 18B and 12C. MS m/z 474 (M+1).Step 2. Preparation of{7-[4-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 26)

The title compound was prepared from the product of Example 26A in themanner analogous to Example 1. mp 220° C. (dec.); 400 MHz ¹H NMR(DMSO-d₆) δ 12.94 (s, 1H), 8.97 (s, 1H), 8.2 (dd, 1H, J=2 Hz, J′=8.8Hz), 8.13 (d, 1H, J=8.4 Hz), 8.01 (d, 2H, J=8.4 Hz), 7.34 (d, 2H, J=8.8Hz), 7.07 (d, 1H, J=8.4 Hz), 6.57 (d, 1H, J=8 Hz), 4.61 (s, 2), 4.07 (s,2H), 2.72 (m, 4H), 1.89 (m, 2H). MS m/z 460 (M+1).

EXAMPLE 27

Synthesis of{5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 27)

Step 1. Preparation of{5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 27A)

The title compound was prepared from the products of Example 18B and(7-mercapto-5-methyl-indan-4-yloxy)-acetic acid methyl ester (preparedin a similar manner as described for Example 12C) in a manner analogousto Example 1F. MS m/z 488 (M+1).Step 2. Preparation of{5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4yloxy}-aceticacid (compound 27)

The title compound was prepared from the product of Example 27A in themanner analogous to Example 1. mp 186° C.; 400 MHz ¹H NMR (DMSO-d₆) δ12.94 (s, 1H), 8.97 (s, 1H), 8.24 (dd, 1H, J=2 Hz, J′=8.8 Hz), 8.14 (d,1H, J=8.4 Hz), 8.01 (d, 2H, J=8.4 Hz), 7.34 (d, 2H, J=8.8 Hz), 6.99 (s,1H), 4.41 (s, 2H), 4.13 (s, 2H), 2.83 (t, 2H, J=7.2 Hz), 2.62 (t, 2H,J=7.2 Hz), 2.13 (s, 3H), 1.87 (m, 2H). MS m/z 474 (M+1).

EXAMPLE 28

Synthesis of[5-Methyl-7-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid (compound 28)

Step 1. Preparation of[5-Methyl-7-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid methyl ester (compound 28A)

The title compound was prepared from the product of Example 3B and(7-Mercapto-5-methyl-indan-4-yloxy)-acetic acid methyl ester in a manneranalogous to Example 1F. MS m/z 487 (M+1).Step 2. Preparation of[5-Methyl-7-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid (compound 28)

The title compound was prepared from the product of Example 28A in themanner analogous to Example 1. mp 177° C.; 400 MHz ¹H NMR (DMSO-d₆) δ12.82 (s, 1H), 7.82(d, 2H, J=8 Hz), 7.75 (d, J=8 Hz), 7.61 (d, 2H, J=8Hz), 7.35 (d, 2H, J=8 Hz), 6.99 (s, 1H), 4.41 (s, 2H), 4.12 (s, 2H),2.83 (t, 2H, J=7.2 Hz), 2.62 (t, 2H, J=7.2 Hz), 2.13 (s, 3H), 1.89 (m,2H). MS m/z 473 (M+1).

EXAMPLE 29

Synthesis of(4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benzylsulfanyl}-5-methoxy-2-methyl-phenoxy)-aceticacid (compound 29)

Step 1. Preparation of {4-[2-(3-Fluoro-phenyl)-vinyl]-phenyl}-methanol(compound 29A)

(4-Bromo-phenyl)-methanol (1 g, 5.35 mmol), 3-fluorostyrene (718 mg,5.89 mmol), palladium acetate (60 mg, 0.3 mmol), and triphenylphosphine(140 mg, 0.6 mmol) were heated in triethylamine at 90° C. in a sealedtube for 18 h. The reaction was concentrated and purified by normalphase chromatography to afford the title compound. MS m/z 227 (M−1).Step 2. Preparation of{4-[2-(3-Fluoro-phenyl)-vinyl]-phenyl}-chloromethane (compound 29B)

The title compound was prepared from the product of Example 29A in amanner analogous to Example 3B. MS m/z 245 (M−1).Step 3. Preparation of(4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benzylsulfanyl}-5-methoxy-2-methyl-phenoxy)-aceticacid methyl ester (compound 29C)

The title compound was prepared from the product of Example 29B and theproduct of Example 1D in a manner analogous to Example 1F. MS m/z 453(M+1).Step 4. Preparation of(4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benzylsulfanyl}-5-methoxy-2-methyl-phenoxy)-aceticacid (compound 29)

The title compound was prepared from the product of Example 29C in themanner analogous to Example 1. mp 154° C. (dec.); 400 MHz ¹H NMR(DMSO-d₆) δ 12.94 (s, 1H), 7.46-7.34 (m, 5H), 7.27-7.15 (m, 4H),7.06-6.99 (m, 2H), 6.52 (s, 1H), 4.69 (s, 2H), 3.98 (s, 2H), 3.73 (s,3H), 2.00 (s, 3H), MS m/z 439 (M+1).

EXAMPLE 30

Synthesis of{2-Methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid (compound 30)

Step 1. Preparation of{2-Methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 30A)

The title compound was prepared from the product of Example 2C and theproduct of Example 18B in a manner analogous to Example 1F. MS m/z 448(M+1).Preparation of{2-Methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid

The title compound was prepared from the product of Example 30A in themanner analogous to Example 1. 400 MHz ¹H NMR (DMSO-d₆) δ 8.97 (s, 1H),8.2 (dd, 1H, J=2 Hz, J′=8.8 Hz), 8.13 (d, 1H, J=8.4 Hz), 8.01 (d, 2H,J=8.4 Hz), 7.36 (d, 2H, J=8.4 Hz), 7.07 (s, 1H), 7.01 (dd, 1H, J=8.4 Hz,J′=2.4 Hz), 6.57 (d, 1H, J=8.8 Hz), 4.09 (s, 2H), 4.06 (s, 2H), 2.04 (s,3H). MS m/z 434 (M+1).

EXAMPLE 31

Synthesis of{4-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid (compound 31)

Step 1. Preparation of [4-(2,4-Difluoro-benzyloxy)phenyl]-methanol(compound 31A)

The title compound was prepared in the manner analogous to Example 14Ausing 1-bromomethyl-2,4-difluoro-benzene and 4-hydroxymethyl-phenol. MSm/z 233 (M-OH).Step 2. Preparation of1-(4-Chloromethyl-phenoxymethyl)-2,4-difluoro-benzene (compound 31B)

The title compound was prepared in the manner analogous to Example 3Busing 31A. MS m/z 233 (M-Cl).Step 3. Preparation of{4-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid methyl ester (compound 31C)

The title compound was prepared in the manner analogous to Example 1Fusing 31B and 2C. MS m/z 445 (M+1).Step 4. Preparation of{4-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid

To a solution of the product from Example 31C (1.5 g, 3.3 mmol) in amixture of 20 mL of tetrahydrofuran and 4 mL of water was added lithiumhydroxide monohydrate (0.42 g, 9.9 mmol). The reaction mixture wasstirred at room temperature for 18 hrs and then evaporated to afford aresidue, which was suspended in 50 mL of water. The mixture wasacidified with 1N hydrochloric acid to pH 2. The precipitated solid wascollected be filtration, washed with water, and then dried to providethe title compound without any further purification. mp 139-141° C.; IR(KBr) cm⁻¹: 3081, 2917, 1735, 1604, 1508, 1233; 400 MHz ¹H NMR(DMSO-d₆): δ 7.51-7.59 (m, 1H), 7.02-7.31 (m, 6H), 6.85-6.92 (m, 2H),6.68 (d, 1H, J=8.6 Hz), 5.01 (s, 2H), 4.60 (s, 2H), 4.00 (s, 2H), 2.08(s, 3H); MS m/z 429 (M−1). Anal. Calc'd for C₂₃H₂₀F₂O₄S: C, 64.17; H,4.68; found: C, 64.11; H, 4.59.

EXAMPLE 32

Synthesis of{4-[4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid (compound 32)

Step 1. Preparation of [4-(2,4-Dichloro-benzyloxy)-phenyl]-methanol(compound 32A)

The title compound was prepared in the manner analogous to Example 14Ausing 2,4-dichloro-1-chloromethyl-benzene and 4-hydroxymethyl-phenol. MSm/z 265 (M-OH).Step 2. Preparation of2,4-Dichloro-1-(4-chloromethyl-phenoxymethyl)-benzene (compound 32B)

The title compound was prepared in the manner analogous to Example 3Busing 32A. MS m/z 265 (M-Cl).Step 3. Preparation of{4-[4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid methyl ester (compound 32C)

The title compound was prepared in the manner analogous to Example 1Fusing 32B and 2C. MS m/z 477 (M+1).Step 4. Preparation of{4-[4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid (compound 32)

The title compound was prepared in the manner analogous to Example 1using 32C. mp 143-145° C.; IR (KBr) cm⁻¹: 3062, 2936, 1724, 1492, 1227,1192; 400 MHz ¹H NMR (DMSO-d₆): δ 12.97 (br(s), 1H), 7.64 (d, 1H, J=2.0Hz), 7.54 (d, 1H, J=8.3 Hz), 7.42 (dd, 1H, J=8.3, 2.0 Hz), 7.01-7.20 (m,4H), 6.84-6.92 (m, 2H), 6.69 (d, 1H, J=8.5 Hz), 5.05 (s, 2H), 4.62 (s,2H), 4.01 (s, 2H), 2.08 (s, 3H); MS m/z 461 (M−1). Anal. Calc'd forC₂₃H₂₀Cl₂O₄S: C, 59.62; H, 4.35; found: C, 59.33; H, 4.28.

EXAMPLE 33

Synthesis of{4-[4-(4-Methoxy-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid (compound 33)

Step 1. Preparation of [4-(4-Methoxy-benzyloxy)-phenyl]-methanol(compound 33A)

The title compound was prepared in the manner analogous to Example 14Ausing 1-chloromethyl-4-methoxy-benzene and 4-hydroxymethyl-phenol. MSm/z 227 (M-OH).Step 2. Preparation of4-Methoxy-1-(4-chloromethyl-phenoxymethyl)-benzene (compound 33B)

The title compound was prepared in the manner analogous to Example 3Busing 33A. MS m/z 227 (M-Cl).Step 3. Preparation of{4-[4-(4Methoxy-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acidmethyl ester (compound 33C)

The title compound was prepared in the manner analogous to Example 1Fusing 33B and 2C. MS m/z 439 (M+1).Step 4. Preparation of{4-[4(4-Methoxy-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid(compound 33)

The title compound was prepared in the manner analogous to Example 1using 33C. mp 150-152° C.; HPLC: area %=96.69, r.t.=2.93 min., γ=214 nm,mobile phase=acetonitrile/water with 0.10% TFA; IR (KBr) cm⁻¹: 2929,1728, 1707, 1513, 1491, 1225; 400 MHz ¹H NMR (DMSO-d₆): δ 12.98 (br(s),1H), 7.27-7.23 (m, 2H), 7.02-7.16 (m, 4H), 6.81-6.91 (m, 4H), 6.69 (d,1H, J=8.6 Hz), 4.91 (s, 2H), 4.61 (s, 2H), 3.99 (s, 2H), 3.69 (s, 3H),2.08 (s, 3H); MS m/z 423 (M−1). Anal. Calc'd for C₂₄H₂₄O₃S: C, 67.90; H,5.70; found: C, 67.48; H, 5.59.

EXAMPLE 34

Synthesis of{4-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid (compound 34)

Step 1. Preparation of [4-(4-tert-Butyl-benzyloxy)-phenyl]-methanol(compound 34A)

The title compound was prepared in the manner analogous to Example 14Ausing 1-bromomethyl-4-tert-butyl-benzene and 4-hydroxymethyl-phenol. MSm/z 253 (M-OH).Step 2. Preparation of4-tert-Butyl-1-(4-chloromethyl-phenoxymethyl)-benzene (compound 34B)

The title compound was prepared in the manner analogous to Example 3Busing 34A. MS m/z 253 (M-Cl).Step 3. Preparation of{4-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid methyl ester (compound 34C)

The title compound was prepared in the manner analogous to Example 1Fusing 34B and 2C. MS m/z 465 (M+1).Step 4. Preparation of{4-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid (compound 34)

The title compound was prepared in the manner analogous to Example 1using 34C. mp 135-137° C.; IR (KBr) cm⁻¹: 2961, 2908, 1751, 1495, 1233,1194; 400 MHz ¹H NMR (DMSO-d₆): δ 13.00 (br(s), 1H), 7.27-7.38 (m, 4H),7.02-7.17 (m, 4H), 6.82-6.88 (m, 2H), 6.69 (d, 1H, J=8.5 Hz), 4.96 (s,2H), 4.61 (s, 2H), 3.99 (s, 2H), 2.08 (s, 3H), 1.22 (s, 9H); MS m/z 451(M+1). Anal. Calc'd for C₂₇H₃₀O₄S: C, 71.97; H, 6.71; found: C, 71.66;H, 6.52.

EXAMPLE 35

Synthesis of{2-Methyl-4-[4-(4-trifluoromethoxy-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid (compound 35)

Step 1. Preparation of[4-(4-Acetoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid methyl ester(compound 35A)

The title compound was prepared in the manner analogous to Example 1Fusing acetic acid 4-chloromethyl-phenyl ester and 2C. MS m/z 361 (M+1).Step 2. Preparation[4-(4Hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid (compound35B)

The title compound was prepared in the manner analogous to Example 1using 35A. MS m/z 303 (M−1).Step 3. Preparation of[4-(4-Hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid methyl ester(compound 35C)

To a solution of the product from Example 35B (0.43 g, 1.4 mmol) in 14mL of 2,2-dimethoxy propane was added 1.4 mL of concentratedhydrochloric acid. The reaction mixture was stirred at room temperaturefor 18 hours. The mixture was concentrated and purified by flashchromatography to provide the title compound. MS m/z 317 (M−1).Step 4. Preparation of{2-Methyl-4-[4(4-trifluoromethoxy-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 35D)

The title compound was prepared in the manner analogous to Example 1Fusing 1-bromomethyl-4-trifluoromethoxy-benzene and 35C. MS m/z 493(M+1).Step 5. Preparation of{2-Methyl-4-[4-(4-trifluoromethoxy-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid (compound 35)

The title compound was prepared in the manner analogous to Example 1using 35D. mp 141-142° C.; 400 MHz ¹H NMR (DMSO-d₆): δ 12.96 (br(s),1H), 7.46-7.57 (m, 2H), 7.28-7.38 (m, 2H), 7.00-7.20 (m, 4H), 6.82-6.91(m, 2H), 6.69 (d, 1H, J=8.6 Hz), 5.05 (s, 2H), 4.62 (s, 2H), 4.00 (s,2H), 2.08 (s, 3H); MS m/z 477 (M−1). Anal. Calc'd for C₂₄H₂₁F₃O₃S: C,60.25; H, 4.42; found: C, 59.92; H, 4.07.

EXAMPLE 36

Synthesis of{6-Methyl-8-[4-(5-trifluoromethyl-pyridine-2-yl)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 36)

Step 1.{6-Methyl-8-[4-(5-trifluoromethyl-pyridine-2-yl)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid methyl ester (compound 36A)

The title compound was prepared in the manner analogous to Example 1Fusing (8-mercapto-6-methyl-chroman-5-yloxy)-acetic acid methyl ester and18B. MS m/z 504 (M+1).Step 2.{6-Methyl-8-[4-(5-trifluoromethyl-pyridine-2-yl)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid methyl ester (compound 36)

The title compound was prepared in the manner analogous to Example 1using 36A. mp 156-157° C.; IR (KBr) cm⁻¹: 2928, 1731, 1710, 1603, 1329,1113, 1082; 400 MHz ¹H NMR (DMSO-d₆): δ 12.84 (br(s), 1H), 8.97 (s, 1H),8.22 (dd, 1H, J=8.4, 2.0 Hz), 8.12 (d, 1H, J=8.4 Hz), 8.04 (d, 2H, J=8.2Hz), 7.42 (d, 2H, J=8.2 Hz), 6.88 (s, 1H), 4.29 (s, 2H), 4.05-4.14 (m,4H), 2.64 (t, 2H, J=6.3 Hz), 2.04 (s, 3H), 1.81 (pentet, 2H); MS m/z 490(M+1). Anal. Calc'd for C₂₅H₂₂F₃NO₄S: C, 61.34; H, 4.53; N, 2.86; found:C, 60.96; H, 4.48; N, 2.79.

EXAMPLE 37

Synthesis of{5-Chloro-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid (compound 37)

Step 1. Preparation of{5-Chloro-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 37A)

Compound 37A was prepared in the manner analogous to Example 1F usingthe products from Example 18B and Example 20C. MS m/z 482 (M+).Step 2. Preparation of{5-chloro-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid (compound 37)The title compound was prepared in the manner analogous to Example 1using 37A. IR cm⁻¹: 1708, 1122; 400 MHz ¹H NMR (DMSO-d₆) δ 8.97 (s, 1H),8.22 (d, 1H, J=8.3 Hz), 8.12 (d, 1H, J=8.3 Hz), 8.04 (d, 2H, J=8.3 Hz),7.43 (d, 2H, J=8.3 Hz), 7.25 (s, 1H), 6.94 (s, 1H), 4.70 (s, 2H), 4.21(s, 2H), 2.06 (s, 3H). Anal. Calc'd for C₂₂H₁₇ClF₃NO₃S; C, 56.47, H,3.66, N 2.99; found: C, 56.48, H, 3.28, N 3.04.

EXAMPLE 38

Synthesis of[5-hydroxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxyl-aceticacid (compound 38)

A solution of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid, prepared according to Example 4,(1.0 g, 2.2 mmol) in 75 mL DCM at0° C. was treated with dropwise addition of BBr₃ (5.5 mL of a 1.0 Msolution in DCM). After 30 minutes, the reaction was carefully quenchedwith 50% NH₄OH. The reaction was then acidified to pH 1 with conc. HCl,and extracted with EtOAc. The organic layer was dried (Na₂SO₄) andconcentrated in vacuo. The crude reaction mixture was then taken up inMeOH, followed by addition of 50 μL H₂SO₄, and then refluxing for 3hours. The reaction was then diluted with EtOAc, washed 1×50 mL water,dried (Na₂SO₄), and the reaction concentrated in vacuo. The resultingester was purified by recrystallization from EtOAC/Hexanes. The esterwas then saponified in the same manner as described for Example 1, togive the title compound in 37% overall yield. IR cm⁻¹:3408, 1752, 1323;400 MHz ¹H NMR (DMSO-d₆) δ 9.56 (s, 1H), 7.82 (d, 2H, J=8.4 Hz), 7.74(d, 2H, J=8.4 Hz), 7.31 (d, 2H, J=8.4 Hz), 6.92 (s, 1H), 6.30 (s, 1H),4.55 (s, 2H), 4.00 (s, 2H), 1.95 (s, 3H). Anal. Calc'd forC₂₃H₁₉F₃NO₄S.0.1 H₂O C, 61.35; H, 4.30; found: C, 61.08; H, 3.92.

EXAMPLE 39

Synthesis of[5-Methoxy-2-methyl-4(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 39)

Step 1. Preparation of(3-Methyl-4′-trifluoromethyl-biphenyl-4-yl)-methanol (compound 39A)

The title compound was prepared in the manner analogous to Example 3Ausing (4-bromo-2-methyl-phenyl)-methanol and4-(trifluoromethyl)benzeneboronic acid. MS m/z 249 (M-OH).Step 2. Preparation of4chloromethyl-3-methyl-4′-trifluoromethyl-biphenyl (compound 39B)

The title compound was prepared in the manner analogous to Example 3Busing 39A. 400 MHz ¹H NMR (DMSO-d₆) δ 7.84 (d, 2H, J=8.3 Hz), 7.76 (d,2H, J=8.3 Hz), 7.57 (s, 1H), 7.48 (m, 2H), 4.80 (s, 2H), 2.41 (s, 3H).Step 3. Preparation of[5-Methoxy-2-methyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid methyl ester (compound 39C)

The title compound was prepared in the manner analogous to Example 1Fusing 1D and 39B. MS m/z 491 (M+1).Step 4. Preparation of[5-Methoxy-2-methyl-4-(methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 39)The title compound was prepared in the manner analogous to Example 1using 39C. IR cm⁻¹: 1740, 1322; 400 MHz ¹H NMR (DMSO-d₆) δ 7.81 (d, 2H,J=8.1 Hz), 7.73 (d, 2H, J=8.1 Hz), 7.51 (s, 1H), 7.39 (d, 1H, J=7.8 Hz),7.16 (d, 1H, J=7.8 Hz), 7.04 (s, 1H), 6.53 (s, 1H), 4.71 (s, 2H), 4.00(s, 2H), 3.73 (s, 3H), 2.39 (s, 3H), 2.02 (s, 3H); MS m/z 477 (M+1).Anal. Calc'd for C₂₅H₂₃F₃O₄S.0.1 H₂O; C, 62.78; H, 4.89; found: C,62.57; H, 4.82.

EXAMPLE 40

Synthesis of{7-[4-(4-trifluoromethyl-benzyl)-benzylsulfanyl]-indan-4yloxy}-aceticacid (compound 40)

Step 1. Preparation of 4-(4-trifluoromethyl-benzyl)-benzoic acid methylester (compound 40A)

A solution of 1-bromo-4-trifluoromethyl-benzene (10.0 g, 44.4 mmol) inTHF at −78° C. was treated with dropwise addition of n-butyl lithium(33.3 mL of a 1.6 M solution in hexanes). After 20 minutes,4-formyl-benzoic acid methyl ester in 50 mL THF was added. The reactionwas allowed to come to room temperature and after 1 H, quenched withsat. NH₄Cl. The reaction was then concentrated in vacuo, taken up inEtOAc, and washed with 2 M HCl (1×100 mL), brine (1×100 mL), dried(Na₂SO₄) and the solvent removed in vacuo to give the alcoholintermediate. Purification by flash column chromatography (gradientelution: 5% EtOAc/hexane to 40% EtOAc/hexane) gave 6.2 g of the alcoholintermediate. 4.0 g (12.9 mmol) of the intermediate was thenhydrogenated in EtOAc using 0.5 g of 10% Pd(OH)₂/C as catalyst.Filtration through Celite®, and concentration in vacuo gave the titlecompound (3.60 g, 95%). MS m/z 295 (M+1).Step 2. Preparation of [4-(4-trifluoromethyl-benzyl)-phenyl]-methanol(compound 40B)

A solution of 40A (3.6 g, 12.2 mmol) in 75 mL THF at room temperaturewas treated portionwise with lithium aluminum hydride (0.97 g, 25.6mmol). After 1 hour, the reaction mixture was carefully quenched withsat. NH₄Cl. The reaction mixture was then extracted with EtOAc, and theorganic layer washed with 2 M HCl (1×50 mL), brine (1×50 mL), dried(Na₂SO₄) and the solvent removed in vacuo. Purification by flash columnchromatography (gradient elution: 5% EtOAc/hexane to 40% EtOAc/hexane)gave the title compound (2.8 g, 86%). MS m/z 265 (M−1).Step 3. Preparation ofChloro-[4-(4-trifluoromethyl-benzyl)-phenyl]-methane (compound 40C)

The title compound was prepared in a similar manner as described for 3Busing 40B and thionyl chloride. 400 MHz ¹H NMR (DMSO-d₆) 7.59 (d, 2H,J=8.4 Hz), 7.40 (d, 2H, J=8.4 Hz), 7.31 (d, 2H, J=8.4 Hz), 7.20 (d, 2H,J=8.4 Hz), 4.67 (s, 2H), 3.99 (s, 2H).Step 4. Preparation of{7-[4-(4-Trifluoromethyl-benzyl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 40D)

The title compound was prepared in the manner analogous to Example 1Fusing the product from Example 12C and Example 40C. MS m/z 487 (M+1).Step 5. Preparation of{7-[4-(4-trifluoromethyl-benzyl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 40)The title compound was prepared in the manner analogous to Example 1using 40D. IR cm⁻¹: 1745, 1704, 1325; 400 MHz ¹H NMR (DMSO-d₆) δ 7.58(d, 2H, J=8.1 Hz), 7.37 (d, 2H, J=8.1 Hz), 7.09 (s, 2H), 7.05 (d, 2H,J=8.3 Hz), 6.55 (d, 1H, J=8.3 Hz), 4.60 (s, 2H), 3.94 (s, 4H), 2.71 (t,2H, J=8.3 Hz), 2.58 (t, 2H, J=8.3 Hz), 1.81 (m, 2H); MS m/z 473 (M+1).Anal. Calc'd for C₂₆H₂₃F₃O₃S.0.1 H₂O, C, 65.84; H, 4.93; found: C,65.58; H, 4.96.

EXAMPLE 41

Synthesis of{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-methoxy-2-methyl-phenoxy}-aceticacid (compound 41)

Step 1. Preparation of{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-methoxy-2-methyl-phenoxy}-aceticacid methyl ester (compound 41A)

The title compound was prepared in the manner analogous to Example 1Fusing 1D and 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole. MS m/z 434(M+1).Step 2. Preparation of{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-methoxy-2-methyl-phenoxy}-aceticacid (compound 41)The title compound was prepared in the manner analogous to Example 1using 41A. IR cm⁻¹: 1747, 1432; 400 MHz ¹H NMR (DMSO-d₆) δ 7.81 (d, 2H,J=8.8 Hz), 7.53 (d, 2H, J=8.8 Hz), 7.05 (s, 1H), 6.92 (s, 1H), 6.52 (s,1H), 4.69 (s, 2H), 4.01 (s, 2H), 3.71 (s, 3H), 2.00 (s, 3H); MS m/z 420(M+1). Anal. Calc'd for C₂₀H₁₈ClNO₅S, C 57.21; H, 4.32 N, 3.34; found:C, 56.84; H, 4.62, N, 2.96.

EXAMPLE 42

Synthesis of{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid (compound 42)

Step 1. Preparation of5-(4-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester(compound 42A)

Sodium hydride (1.6 g, 63.7 mmol, 95%) was added to a solution of1(4-trifluoromethyl-phenyl)-ethanone (10.0 g, 53.1 mmol) and oxalic aciddiethyl ester (8.7 mL, 63.7 mmol) in 75 mL dry DMF at 0° C. The reactionwas allowed to come to room temperature and then heated to 45° C. for 45minutes. The reaction was then cooled, concentrated in vacuo, and theresidue taken up in EtOAc. The organic layer was then washed with 2 MHCl (1×100 mL), dried (Na₂SO₄) and the solvent removed in vacuo.Purification by flash column chromatography (gradient elution: 5%EtOAc/hexane to 55% EtOAc/hexane) gave the intermediate2,4-dioxo-4-(4-trifluoromethyl-phenyl)-butyric acid ethyl ester (12.2 g,80%) which was then taken up in EtOH and refluxed in the presence ofhydroxyl amine hydrochloride (10.2 g, 132.3 mmol) for 3H. The reactionwas then cooled, diluted with EtOAc, washed with dilute NaHCO₃, brine,dried (Na₂SO₄), and concentrated in vacuo. Recrystallization fromEtOAc/hexane gave 5.2 g of the title compound. MS m/z 286 (M+1).Step 2. Preparation of[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-yl]-methanol (compound 42B)

The title compound was prepared in a manner analogous to Example 40Busing 42A. MS m/z 244 (M+1).Step 3. Preparation of3-chloromethyl-5-(4-trifluoromethyl-phenyl)-isoxazole (compound 42C)

The title compound was prepared in a manner analogous to Example 3Busing 42B. MS m/z 262 (M+1).Step 4. Preparation of{2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 42

The title compound was prepared in a manner analogous to Example 1Fusing 42C and 2C. MS m/z 438 (M+1).Step 5. Preparation of{2Methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid (compound 42)The title compound was prepared in a manner analogous to Example 1 using42D. IR cm⁻¹:1746, 1326; 400 MHz ¹H NMR (DMSO-d₆) δ 12.97 (br(s), 1H),8.02 (d, 2H, J=8.0 Hz), 7.83 (d, 2H, J=8.0 Hz), 7.20 (s, 1H), 7.15 (s,2H), 6.71 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 4.14 (s, 2H), 2.08 (s, 3H);MS m/z 424 (M+1). Anal. Calc'd for C₂₀H₁₆F₃NO₄S C, 56.73; H, 3.81; N,3.31 found: C, 56.59; H, 3.58; N, 3.22.

EXAMPLE 43

Synthesis of{5-Methoxy-2methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid (compound 43)

Step 1. Preparation of{5-Methoxy-2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 43A)

The title compound was prepared in a manner analogous to Example 1Fusing 42C and 1D. MS m/z 468 (M+1).Step 2. Preparation of{5-Methoxy-2-methyl-4-15-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid (compound 43)The title compound was prepared in a manner analogous to Example 1 using43A. IR cm⁻¹: 1745, 1322; 400 MHz ¹H NMR (DMSO-d₆) δ 12.96 (br(s), 1H),8.01 (d, 2H, J=8.3 Hz), 7.83 (d, 2H, J=8.3 Hz), 7.07 (s, 2H), 6.52 (s,1H), 4.70 (s, 2H), 4.03 (s, 2H), 3.71 (s, 3H), 1.99 (s, 3H); MS m/z 454(M+1). Anal. Calc'd for C₂₁H₁₈F₃NO₃S. 0.1H₂O C, 54.46; H, 3.92; N, 3.01found: C, 54.54; H, 3.74; N, 2.93.

EXAMPLE 44

Synthesis of{7-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 44)

Step 1. Preparation of{7-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 44A)

The title compound was prepared in a manner analogous to Example 1Fusing 42C and 12C. MS m/z 464 (M+1).Step 2. Preparation of{7-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 44)The title compound was prepared in a manner analogous to Example 1 using44A. 400 MHz ¹H NMR (DMSO-d₆) δ 12.94 (br(s), 1H), 8.01 (d, 2H, J=8.4Hz), 7.83 (d, 2H, J=8.4 Hz), 7.09 (s, 2H), 6.58 (d, 1H, J=8.6 Hz), 4.62(s, 2H), 4.08 (s, 2H), 2.77 (m, 4H), 1.89 (m, 2H); MS m/z 450 (M+1).Anal. Calc'd for C₂₂H₁₈F₃NO₄S C, 58.79; H, 4.04; N, 3.12 found: C,58.59; H, 3.80; N, 3.01.

EXAMPLE 45

Synthesis of{2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid (compound 45)

Step 1. Preparation of5-chloromethyl-3-(4-trifluoromethyl-phenyl)-isoxazole (compound 45A)

A solution of 4-trifluoromethyl-benzaldehyde oxime (8.9 g, 47.1 mmol) in100 mL DCM was added to a rapidly stirred solution of propargyl chloride(47.1 mmol), triethyl amine (4.71 mmol) and 91 mL of commercial bleach(6.5% by weight) all in 50 mL DCM at 0° C. After 1 hour the layers wereseparated and the organic layer dried (Na₂SO₄), and concentrated invacuo. Purification by flash column chromatography (gradient elution: 5%EtOAc/hexane to 25% EtOAc/hexane) gave the title compound (2.9 g, 23%)MS m/z 262 (M+1).Step 2. Preparation of{2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 45B)

The title compound was prepared in a manner analogous to Example 1Fusing 45A and 2C. MS m/z 438 (M+1).Step 3. Preparation of{2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-3-phenoxy}-aceticacid (compound 45)The title compound was prepared in a manner analogous to Example 1 using45B. IR cm⁻¹: 1747; 400 MHz ¹H NMR (DMSO-d₆) δ 12.97 (br(s), 1H), 7.99(d, 2H, J=8.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.21 (s, 1H), 7.16 (d, 1H,J=8.5 Hz), 6.86 (s, 1H), 6.74 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 4.30 (s,2H), 2.09 (s, 3H); MS m/z 424 (M+1).

EXAMPLE 46

Synthesis of{5-Methoxy-2-methyl-4-[3(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid (compound 46)

Step 1. Preparation of{5-Methoxy-2-methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 46A)

The title compound was prepared in a manner analogous to Example 1Fusing 45A and 1D. MS m/z 468 (M+1).Step 2. Preparation of{5-Methoxy-2-methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid (compound 46)The title compound was prepared in a manner analogous to Example 1 using46A. IR cm⁻¹:1752, 1711; 400 MHz ¹H NMR (DMSO-d₆) δ 12.96 (br(s), 1H),7.98 (d, 2H, J=8.1 Hz), 7.81 (d,2H, J=8.1 Hz), 7.09 (s, 1H), 6.80 (s,1H), 6.54 (s, 1H), 4.71 (s, 2H), 4.18 (s, 2H), 3.79 (s, 3H), 2.00 (s,3H); MS m/z 454 (M+1).

EXAMPLE 47

Synthesis of [2-Methyl-4-(4-phenoxy-benzylsulfanyl)-phenoxy]-acetic acid(compound 47)

Step 1. Preparation of[2-Methyl-4-(4-phenoxy-benzylsulfanyl)-phenoxy]-acetic acid methyl ester(compound 47A)

The title compound was prepared in the manner analogous to Example 1Fusing 1-chloromethyl-4-phenoxy-benzene and 2C. MS m/z 321(M-methylacetate).Step 2. Preparation of[2-Methyl-4-(4-phenoxy-benzylsulfanyl)-phenoxy]-acetic acid (compound47)The title compound was prepared in the manner analogous to Example 1using 47A. 400 MHz ¹H NMR (DMSO-d₆) δ 12.95 (br(s), 1H), 7.33 (m, 2H),7.22 (m, 2H), 7.07 (m, 3H), 6.93 (m, 2H), 6.87 (m, 2H), 6.71 (d, 1H,J=8.3 Hz), 4.62 (s, 2H), 4.04 (s, 2H), 2.09 (s, 3H). MS m/z 379 (M−1).

EXAMPLE 48

Synthesis of[7-(4′-Trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid (compound 48)

Step 1. Preparation of (4′-Trifluoromethyl-biphenyl-3-yl)-methanol(compound 48A)

The title compound was prepared in the manner analogous to Example 3Awith 1-bromo-4-trifluoromethyl-benzene and 3-(hydroxymethyl)phenylboronic acid. MS m/z 251 (M−1).Step 2. Preparation of 3-Chloromethyl-4′-trifluoromethyl-biphenyl(compound 48B)

The title compound was prepared in the manner analogous to Example 3Busing 48A. MS m/z 236 (M+1-Cl).Step 3. Preparation of[7-(4′-Trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid methyl ester (compound 48C)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 48B. MS m/z 473 (M+1).Step 4. Preparation of[7-(4′-Trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid (compound 48)The title compound was prepared in the manner analogous to Example 1using 48C. 400 MHz ¹H NMR (DMSO-d₆) δ 12.96 (br(s), 1H), 7.75 (d, 2H,J=8.3 Hz), 7.67 (d, 2H, J=8.1 Hz), 7.52 (m, 1H), 7.37 (t, 1H, J=7.6 Hz),7.29 (m, 2H), 7.13 (d, 1H, J=8.5 Hz), 6.61 (d, 1H, J=8.5 Hz), 4.63 (s,2H), 4.05 (s, 2H), 2.71 (t, 2H), 2.58 (t, 2H), 1.81 (m, 2H). MS m/z 459(M+1).

EXAMPLE 49

Synthesis of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 49)

Step 1. Preparation of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid methyl ester (compound 49A)

The title compound was prepared in the manner analogous to Example 1Fusing 48B and 1D. MS m/z 477 (M+1).Step 2. Preparation of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 49)The title compound was prepared in the manner analogous to Example 1using 49A. 400 MHz ¹H NMR (DMSO-d₆) δ 12.96 (br(s), 1H), 7.73 (d, 2H,J=9 Hz), 7.71 (d, 2H, J=9 Hz), 7.50 (m, 1H), 7.42 (m, 1H), 7.36 (t, 1H,J=7.8 Hz), 7.28 (m, 1H), 6.99 (s, 1H), 6.53 (s, 1H), 4.70 (s, 2H), 4.03(s, 2H), 3.73 (s, 3H), 1.99 (s, 3H). MS m/z 463 (M+1).

EXAMPLE 50

Synthesis of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethanesulfonyl)-phenoxy]-aceticacid (compound 50)

Step 1. Preparation of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethanesulfonyl)-phenoxy]-aceticacid methyl ester (compound 50A)

Example 4 (200 mg) was dissolved in 5 ml dichloromethane. Excessm-chloroperbenzoic acid (300 mg) was added and the reaction was allowedto stir 3 h. The solvent was removed under vacuum and the crude productwas purified by MPLC. MS m/z 509 (M+1).Step 2. Preparation of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethanesulfonyl)-phenoxy]-aceticacid (compound 50)The title compound was prepared in the manner analogous to Example 1using 50A. 400 MHz ¹H NMR (DMSO-d₆) δ 13.13 (br(s), 1H), 7.85 (d, 2H,J=8.1 Hz), 7.77 (d, 2H, J=8.3 Hz), 7.66 (d, 2H, J=8.6 Hz), 7.3 (m, 3H),6.76 (s, 1H), 4.89 (s, 2H), 4.67 (s, 2H), 3.96 (s, 3H), 2.04 (s, 3H). MSm/z 495 (M+1).

EXAMPLE 51

Synthesis of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethanesulfinyl)-phenoxy]-aceticacid (compound 51)

Step 1. Preparation of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethanesulfinyl)-phenoxy]-aceticacid methyl ester (compound 51A)

Example 4 (0.5 g, 1.0 mmol) was dissolved in 25 ml dichloromethanefollowed by the addition of 2-benzenesulfonyl-3-phenyl-oxaziridine(0.274, 1.04 mmol). The reaction was stirred 1 h. 10 ml water was added,the layers were separated, and dichloromethane solution was dried overanhydrous sodium sulfate, decanted, and concentrated. The product wasrecrystallized from ethyl acetate to give the title product. MS m/z 493(M+1).Step 2. Preparation of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethanesulfinyl)-phenoxy]-aceticacid (compound 51)The title compound was prepared in the manner analogous to Example 1using 51A. 400 MHz ¹H NMR (DMSO-d₆) δ 7.83 (d, 2H, J=8.78 Hz), 7.76 (d,2H, J=8.30 Hz), 7.59 (d, 2H, J=8.30 Hz), 7.11 (d, 2H, J=8.30 Hz), 7.02(s, 1H), 6.64 (s, 1H), 4.79 (s, 2H), 4.20 (d, 1H, J=12.7 Hz), 3.91 (d,1H, J=12.4 Hz), 3.76 (s, 3H), 2.03 (s, 3H). MS m/z 479 (M+1).

EXAMPLE 52

Synthesis of[2-Propyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 52)

Step 1. Preparation of[2-Propyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid methyl ester (compound 52A)

The title compound was prepared in the manner analogous to Example 1Fusing 48B and (4-Mercapto-2-propyl-phenoxy)-acetic acid methyl ester,prepared from 2-propylphenol in a manner analogous to Example 2. MS m/z475 (M+1).Step 2. Preparation of[2-Propyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid (compound 52)The title compound was prepared in the manner analogous to Example 1using 52A. 400 MHz ¹H NMR (DMSO-d₆) δ 7.81 (d, 2H, J=8.5 Hz), 7.74 (d,2H, J=8.5 Hz), 7.60 (d, 2H, J=8.1 Hz), 7.33 (d, 2H, J=8.3 Hz), 7.10 (m,1H), 7.02 (m, 1H), 6.71 (d, 1H, J=8.5 Hz), 4.60 (s, 2H), 4.11 (s, 2H),1.43 (m, 2H), 0.77 (m, 3H). MS m/z 459 (M−1).

EXAMPLE 53

Synthesis of{7-[3-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 53)

Step 1. Preparation of[3-(5-Trifluoromethyl-pyridin-2-yl)-phenyl]-methanol (compound 53A)

The title compound was prepared in the manner analogous to Example 3Ausing 3-(hydroxymethyl)phenyl boronic acid and2-chloro-5-trifluoromethyl-pyridine. MS m/z 253 (M+1).Step 2. Preparation of2-(3-Chloromethyl-phenyl)-5-trifluoromethyl-pyridine (compound 53B)

The title compound was prepared in the manner analogous to Example 3Busing 53A. MS m/z 237 (M+1-Cl).Step 3. Preparation of{7-[3-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 53C)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 53B. MS m/z 474 (M+1).Step 4. Preparation of {7-[3-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 53)The title compound was prepared in the manner analogous to Example 1using 53C. 400 MHz ¹H NMR (DMSO-d₆) δ 8.98 (m, 1H), 8.23 (dd, 1H, J=1.7Hz, J′=8.5 Hz), 7.99 (m, 2H), 7.87 (s, 1H), 7.39 (t, 1H, J=7.6 Hz), 7.33(m, 1H), 7.11 (d, 1H, J=8.5 Hz), 6.58 (d, 1H, J=8.5 Hz), 4.61 (s, 2H),4.08 (s, 2H), 2.70 (t, 2H, J=7.3 Hz), 2.63 (t, 2H, J=7.6 Hz), 1.84 (m,2H). MS m/z 460 (M+1).

EXAMPLE 54

Synthesis of(5-Methoxy-2-methyl-4-{2-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-ethylsulfanyl}-phenoxy)-aceticacid (compound 54)

Step 1. Preparation of{4-[2-(1H-Indol-3-yl)-ethylsulfanyl]-5-methoxy-2-methyl-phenoxy}-aceticacid methyl ester (compound 54A)

The compound 1D (1.622 g, 6.7 mmol) and 3-(2-bromo-ethyl)-1H-indole(1.50 g, 6.69 mmol) was dissolved in 5 ml DMF. Potassium carbonate (1.11g, 8.03 mmol) was added followed by stirring at room temperature for 3h. The reaction was filtered, concentrated and purified by MPLC to givethe title compound. MS m/z 225 (M+1).Step 2. Preparation of(5-Methoxy-2-methyl-4-{2-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-ethylsulfanyl}-phenoxy)-aceticacid methyl ester (compound 54B)

The compound 54A (0.300 g, 0.778 mmol) was dissolved in 5 ml DMF. NaHwas added and stirred for ½ h. 4-trifluoromethylbenzyl bromide (0.223 g,0.934 mmol) was added and the reaction was stirred for 1.5 h. 10 ml 2NHCl was added to pH<4. The DMF solution was partitioned between 30 mlwater and 30 ml ethyl acetate. The organic solution was washed 2×30 mlwater 1×30 ml brine, dried over sodium sulfate, decanted, concentratedand purified by MPLC to give the title product. MS m/z 544 (m+1).Step 3. Preparation of(5-Methoxy-2-methyl-4-{2-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-ethylsulfanyl}-phenoxy)-aceticacid (compound 54)The title compound was prepared in the manner analogous to Example 1using 54B. 400 MHz ¹H NMR (DMSO-d₆) δ 13.0 (br(s), 1H), 7.60 (d, 1H,J=8.1 Hz), 7.42 (d, 1H, J=7.96 Hz), 7.31 (m, 4H), 7.04 (m, 2H), 6.96 (m,1H), 6.53 (s, 1H), 5.43 (s, 2H), 4.70 (s, 2H), 3.72 (s, 3H), 3.03 (t,2H, J=8.8 Hz), 2.86 (t, 2H, J=7.6 Hz), 2.04 (s, 3H). MS m/z 530 (M+1).

EXAMPLE 55

Synthesis of[7-(4′-Trifluoromethyl-biphenyl-2-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid (compound 55)

Step 1. Preparation of[7-(4′-Trifluoromethyl-biphenyl-2-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid methyl ester (compound 55A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C, and 2-chloromethyl-4′-trifluoromethyl-biphenyl, which wasprepared in a manner analogous to Examples 3A and 3B. MS m/z 473 (M+1).Step 2. Preparation of[7-(4′-Trifluoromethyl-biphenyl-2-ylmethylsulfanyl)-indan-4-yloxy]-aceticacid (compound 55)The title compound was prepared in the manner analogous to Example 1using 55A. 400 MHz ¹H NMR (DMSO-d₆) δ 12.97 (br(s), 1H), 7.68 (d, 2H,J=8.5 Hz), 7.32 (m, 5H), 7.11 (m, 1H), 6.77 (d, 1H, J=8.5 Hz), 6.47 (d,1H, J=8.3 Hz), 4.62 (s, 2H), 3.87 (s, 2H), 2.70 (m, 2H), 1.76 (m, 2H).MS m/z 459 (M+1).

EXAMPLE 56

Synthesis of{5-Methoxy-2-methyl-4-[2-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid (compound 56)

Step 1. Preparation of{5-Methoxy-2-methyl-4-[2-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 56A)

The title compound was prepared in the manner analogous to Example 1Fusing 81A and 1D. MS m/z 507 (M+1).Step 2. Preparation of5-Methoxy-2-methyl-4-[2-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid (compound 56)The title compound was prepared in the manner analogous to Example 1using 56A. 400 MHz ¹H NMR (DMSO-d₆) δ 12.95 (br(s), 1H), 7.67 (m, 4H),7.12 (m, 2H), 6.96 (m, 2H), 6.80 (m, 1H), 6.49 (s, 1H), 5.19 (s, 2H),4.68 (s, 2H), 3.99 (s, 2H), 3.67 (s, 3H), 1.96 (s, 3H). MS m/z 493(M+1).

EXAMPLE 57

Synthesis of{4-[4-(4-Fluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid(compound 57)

Step 1. Preparation of [4-(4-Fluoro-benzyloxy)-phenyl]-methanol(compound 57A)

The title compound was prepared in the manner analogous to Example 14Ausing 1-bromomethyl-4-fluoro-benzene and 4-hydroxymethyl-phenol. MS m/z215 (M-OH).Step 2. Preparation of1-(4-Chloromethyl-phenoxymethyl)-4difluoro-benzene (compound 57B)

The title compound was prepared in the manner analogous to Example 3Busing 57A. MS m/z 215 (M-Cl).Step 3. Preparation of{4-[4-(4-Fluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acidmethyl ester (compound 57C)

The title compound was prepared in the manner analogous to Example 1Fusing 57B and 2C. MS m/z 427 (M+1).Step 4. Preparation of{4-[4-(4-Fluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid(compound 57)The title compound was prepared in the manner analogous to Example 1using the product from Example 57C. mp 154-155° C.; IR (KBr) cm⁻¹: 3060,2925, 1727, 1495, 1228, 1156; 400 MHz ¹H NMR (DMSO-d₆): δ 13.00 (br(s),1H), 7.37-7.48 (m, 2H), 6.99-7.22 (m, 6H), 6.80-6.90 (m, 2H), 6.69 (d,1H, J=8.5 Hz), 4.98 (s, 2H), 4.61 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H);MS m/z 411 (M−1). Anal. Calc'd for C₂₃H₂₁FO₄S: C, 66.97; H, 5.13; found:C, 66.64; H, 4.88.

EXAMPLE 58

Synthesis of{4-[4-(4-Chloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid(compound 58)

Step 1. Preparation of{4-[4(4-Chloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acidmethyl ester (compound 58A)

The title compound was prepared in the manner analogous to Example 1Fusing I-bromomethyl-4-chloro-benzene and the product from Example 35C.MS m/z 443 (M+1).Step 2. Preparation of{4-[4-(4-Chloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid(compound 58)The title compound was prepared in the manner analogous to Example 1using 58A. mp 164° C.; IR (KBr) cm⁻¹: 3062, 1727, 1612, 1493, 1226,1193; 400 MHz ¹H NMR (DMSO-d₆): δ 12.99 (br(s), 1H), 7.36-7.44 (m, 4H),7.01-7.17 (m, 4H), 6.81-6.89 (m, 2H), 6.69 (d, 1H, J=8.5 Hz), 5.02 (s,2H), 4.61 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H); MS m/z 427 (M−1); Anal.Calc'd for C₂₃H₂₁ClO₄S: C, 64.40; H, 4.93; found: C, 64.43; H, 4.81.

EXAMPLE 59

Synthesis of4-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid (compound 59)

Step 1. Preparation of{4-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid methyl ester (compound 59A)

The title compound was prepared in the manner analogous to Example 1Fusing 2-bromomethyl-1,4-dichloro-benzene and the product prepared fromExample 35C. m/z 265 (M−211).Step 2. Preparation of{4-[4-(2,4-Dichlorobenzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid (compound 59)The title compound was prepared in the manner analogous to Example 1using 59A. mp 101-103° C.; IR (KBr) cm⁻¹: 3077, 1715, 1608, 1496, 1437,1234; 400 MHz ¹H NMR (DMSO-d₆): δ 7.37-7.63 (m, 3H), 6.99-7.20 (m, 4H),6.85-6.94 (m, 2H), 6.63 (d, 1H, J=8.5 Hz), 5.05 (s, 2H), 4.45 (s, 2H),3.99 (s, 2H), 2.07 (s, 3H); HPLC: area %=97.61, r.t.=5.56 min., λ=214nm, mobile phase=acetonitrile/water with 0.10% TFA; MS m/z 461 (M−1).Anal. Calc'd for C₂₃H₂₀Cl₂O₄S: C, 59.62; H, 4.35; found: C, 58.04; H,4.26.

EXAMPLE 60

Synthesis of{2-Methyl-4-[4-(pyridine-2-ylmethoxy)-benzylsulfanyl]-phenoxy}-aceticacid (compound 60)

Step 1. Preparation of{2-Methyl-4-[4-(pyridine-2-ylmethoxy)-benzylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 60A)

The title compound was prepared in the manner analogous to Example 1Fusing 2-bromomethyl-pyridine hydrochloride and the product prepared fromExample 35C. MS m/z 410 (M+1).Step 2. Preparation of{2-Methyl-4-[4-(pyridine-2-ylmethoxy)-benzylsulfanyl]-phenoxy}-aceticacid (compound 60)The title compound was prepared in the manner analogous to Example 1using 60A. mp 150° C.; IR (KBr) cm⁻¹: 2917, 1723, 1605, 1511, 1490,1217;400 MHz ¹H NMR (DMSO-d₆): δ 12.95 (brs, 1H), 8.49-8.55 (s, 1H),7.73-7.81 (m, 1H), 7.40-7.48 (m, 1H), 7.24-7.33 (m, 1H), 7.00-7.19 (m,4H), 6.83-6.93 (m, 2H), 6.69 (d, 1H, J=8.5 Hz), 5.08 (s, 2H), 4.62 (s,2H), 4.00 (s, 2H), 2.08 (s, 3H); HPLC: area %=96.24, r.t.=1.95 min.,γ=214 nm, mobile phase=acetonitrile/water with 0.10% TFA; MS m/z 396(M+1). Anal. Calc'd for C₂₂H₂₁NO₄S: C, 66.82; H, 5.35; N, 3.54; found:C, 66.12; H, 5.09; N, 3.44.

EXAMPLE 61

Synthesis of{5-Chloro-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-aceticacid (compound 61)

Step 1. Preparation of(5-Chloro-2-methyl-4-[4-(4trifluoromethyl-benzyloxy)-benzyl-sulfanyl]-phenoxy}-aceticacid methyl ester (compound 61A)

The title compound was prepared in the manner analogous to Example 1Fusing 14B and 20C. MS m/z 265 (M−245).Step 2. Preparation of{5-Chloro-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzyl-sulfanyl]-phenoxy}-aceticacid (compound 61)The title compound was prepared in the manner analogous to Example 1using 61A. mp 142-143° C.; IR (KBr) cm⁻¹: 3074, 1747, 1321, 1234, 1175,1124; 400 MHz ¹H NMR (DMSO-d₆): δ 13.01 (br(s), 1H), 7.67-7.73 (m, 2H),7.57-7.64 (m, 2H), 7.16-7.25 (m, 4H), 6.87-6.95 (m, 4H), 5.15 (s, 2H),4.69 (s, 2H), 4.07 (s, 2H), 2.07 (s, 3H); MS m/z 495 (M−1). Anal. Calc'dfor C₂₄H₂₀ClF₃O₄S: C, 58.01; H, 4.06; found: C, 57.73; H, 4.06.

EXAMPLE 62

Synthesis of{7-[4-(2,4Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid(compound 62)

Step 1. Preparation of{7-[4(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acidmethyl ester (compound 62A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 4chloromethyl-(2,4-dichloro-benzyloxy-benzene) preparedfrom 4-hydroxymethyl-phenol and 1-chloromethyl-2,4-dichloro-benzene inthe manner analogous to Examples 14A and 14B. MS m/z 503 (M+1).Step 2. Preparation of{7-[4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 62)The title compound was prepared in the manner analogous to Example 1using 62A. mp 149-150° C.; IR (KBr) cm⁻¹: 3089, 1734, 1512, 1473, 1295,1234; 400 MHz ¹H NMR (DMSO-d₆): δ 13.11 (br(s), 1H), 7.40-7.71 (m, 3H),6.88-7.19 (m, 5H), 6.58 (d, 1H, J=8.5 Hz), 5.07 (s, 2H), 4.61 (s, 2H),3.96 (s, 2H), 2.77 (t, 2H, J=7.4 Hz), 2.69 (t, 2H, J=7.4 Hz), 1.91(pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C₂₅H₂₂Cl₂O₄S: C, 61.35;H, 4.53; found: C, 60.95; H, 4.41.

EXAMPLE 63

Synthesis of{7-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 63)

Step 1. Preparation of{7-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 63A)

The title compound was prepared in the manner analogous to Example 1Fusing 14B and 12C. MS m/z 265 (M−237).Step 2. Preparation of{7-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 63)The title compound was prepared in the manner analogous to Example 1using 63A. mp 145° C.; IR (KBr) cm⁻¹: 2968, 1740, 1510, 1325, 1248,1110; 400 MHz ¹H NMR (DMSO-d₆): δ 12.99 (br(s), 1H), 7.66-7.75 (m, 2H),7.55-7.65 (m, 2H); 7.01-7.15 (m, 3H) 6.83-6.90 (m, 2H), 6.56 (d, 1H,J=8.5 Hz), 5.14 (s, 2H), 4.60 (s, 2H), 3.93 (s, 2H), 2.74 (t, 2H, t,J=7.6 Hz), 2.65 (t, 2H, J=7.4 Hz), 1.87 (pentet, 2H); MS m/z 487 (M−1).Anal. Calc'd for C₂₆H₂₃F₃O₄S: C, 63.92; H, 4.75; found: C, 63.95; H,4.65.

EXAMPLE 64

Synthesis of{5-Methyl-7-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 64)

Step 1. Preparation of{5-Methyl-7-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 64A)

The title compound was prepared in the manner analogous to Example 1Fusing 14B and (7-mercapto-5-methyl-indan-4-yloxy)-acetic acid methylester, which was prepared in a similar manner as described for Example12C. MS m/z 265 (M−251).Step 2. Preparation of{5-Methyl-7-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 64)The title compound was prepared in the manner analogous to Example 1using 64A. mp 165-167° C.; IR (KBr) cm⁻¹: 3039, 1707, 1516, 1329, 1163,1112; 400 MHz ¹H NMR (DMSO-d₆) δ 12.81 (br(s), 1H), 7.66-7.74 (m, 2H),7.56-7.64 (m, 2H); 7.11-7.19 (m, 2H), 6.94 (s, 1H), 6.85-6.91 (m, 2H),5.15 (s, 2H), 4.40 (s, 2H), 3.99 (s, 2H), 2.81 (t, 2H, J=7.4 Hz), 2.59(t, 2H, J=7.4 Hz), 2.13 (s, 3H), 1.86 (pentet, 2H); MS m/z 501 (M−1).Anal. Calc'd for C₂₇H₂₃F₃O₄S: C, 64.53; H, 5.01; found: C, 64.33; H,4.82.

EXAMPLE 65

Synthesis of{7-[4-(4-Fluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 65)

Step 1. Preparation of{7-[4-(4-Fluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 65A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 4-chloromethyl-(4-fluoro-benzyloxy-benzene), prepared from4-hydroxymethyl-phenol and 1-bromomethyl-4-fluoro-benzene in a manneranalogous to Examples 14A and 14B. MS m/z 453 (M+1).Step 2. Preparation of{7-[4-(4-Fluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 65)The title compound was prepared in the manner analogous to Example 1using 65A. mp 153-155° C.; IR (KBr) cm⁻¹: 3117, 3028, 1731, 1512, 1471,1231; 400 MHz ¹H NMR (DMSO-d₆): δ 12.94 (br(s), 1H), 7.39-7.47 (m, 2H),7.01-7.20 (m, 5H); 6.82-6.89 (m, 2H) 6.56 (d, 1H, J=8.4 Hz), 4.99 (s,2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.75 (t, 2H, J=7.5 Hz), 2.67 (t, 2H,J=7.5 Hz), 1.89 (pentet, 2H); MS m/z 437 (M−1). Anal. Calc'd forC₂₅H₂₃FO₄S: C, 68.48; H, 5.29; found: C, 68.24; H, 5.15.

EXAMPLE 66

Synthesis of{7-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 66)

Step 1. Preparation of{17-[4(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 66A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 4chloromethyl-(2,4-difluoro-benzyloxy-benzene) preparedfrom 4-hydroxymethyl-phenol and 1-bromomethyl-2,4-difluoro-benzene inthe manner analogous to Examples 14A and 14B. MS m/z 471 (M+1).Step 2. Preparation of{7-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 66)The title compound was prepared in the manner analogous to Example 1using 66A. mp 158-160° C.; IR (KBr) cm⁻¹: 3065, 3043, 1751, 1510, 1433,1239; 400 MHz ¹H NMR (DMSO-d₆): δ 12.94 (br(s), 1H), 7.51-7.61 (m, 1H),7.21-7.30 (m, 1H); 7.01-7.16 (m, 4H) 6.83-6.92 (m, 2H), 6.57 (d, 1H,J=8.5 Hz), 5.01 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.76 (t, 2H, J=7.4Hz), 2.68 (t, 2H, J=7.4 Hz), 1.90 (pentet, 2H); MS m/z 455 (M−1). Anal.Calc'd for C₂₅H₂₂F₂O₄S: C, 65.78; H, 4.86; found: C, 65.58; H, 4.83.

EXAMPLE 67

Synthesis of{7-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 67)

Step 1. Preparation of{7-[4(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acidmethyl ester (compound 67A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 4-chloromethyl-(4-tert-butyl-benzyloxy-benzene) preparedfrom 4-hydroxymethyl-phenol and 1-bromomethyl-4-tert-butyl-benzene inthe manner analogous to Examples 14A and 14B. m/z 491 (M+1).Step 2. Preparation of{7-[4(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid(compound 67)The title compound was prepared in the manner analogous to Example 1using 67A. mp 152-153° C.; IR (KBr) cm⁻¹: 3134, 3032, 1745, 1708, 1473,1228; 400 MHz ¹H NMR (DMSO-d₆): δ 12.94 (br(s), 1H), 7.25-7.39 (m, 4H),7.01-7.14 (m, 3H), 6.80-6.89 (m, 2H), 6.57 (d, 1H, J=8.5 Hz), 4.97 (s,2H), 4.61 (s, 2H), 3.93 (s, 2H), 2.75 (t, 2H, J=7.5 Hz), 2.67 (t, 2H,J=7.5 Hz), 1.89 (pentet, 2H), 1.22 (s, 9H); MS m/z 475 (M−1). Anal.Calc'd for C₂₉H₃₂O₄S: C, 73.08; H, 6.77; found: C, 72.97; H, 6.84.

EXAMPLE 68

Synthesis of{7-[4-(4-Methoxy-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid(compound 68)

Step 1. Preparation of{7-[4-(4-Methoxy-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acidmethyl ester (compound 68A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 4-chloromethyl-(4-methoxy-benzyloxy-benzene) prepared from4-hydroxymethyl-phenol and 1-bromomethyl-4-methoxy-benzene in the manneranalogous to Examples 14A and 14B. MS m/z 465 (M+1).Step 2. Preparation of{7-[4-(4-Methoxy-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid(compound 68)The title compound was prepared in the manner analogous to Example 1using 68A. mp 183-185° C.; IR (KBr) cm⁻¹: 3015, 2588, 1742, 1716, 1514,1243; 400 MHz ¹H NMR (DMSO-d₆): δ 12.97 (br(s), 1H), 7.26-7.34 (m, 2H),7.06-7.13 (m, 2H) 7.04 (d, 1H, J=8.5 Hz), 6.80-6.92 (m, 4H), 6.56 (d,1H, J=8.5 Hz), 4.92 (s, 2H), 4.60 (s, 2H), 3.93 (s, 2H), 3.69 (s, 3H),2.75 (t, 2H, J=7.3 Hz), 2.67 (t, 2H, J=7.3 Hz), 1.89 (pentet, 2H); MSm/z 449 (M−1). Anal. Calc'd for C₂₆H₂₆O₅S: C, 69.31; H, 5.82; found: C,69.00; H, 5.74.

EXAMPLE 69

Synthesis of [7-(4Benzyloxy-benzylsulfanyl)-indan-4-yloxy]-acetic acid(compound 69)

Step 1. Preparation of[7-(4-Benzyloxy-benzylsulfanyl)-indan-4-yloxy]-acetic acid methyl ester(compound 69A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 1-benzyloxy-4-chloromethyl-benzene prepared from4-hydroxymethyl-phenol and 4-bromomethyl-benzene in the manner analogousto Examples 14A and 14B. MS m/z 435 (M+1).Step 2. Preparation of[7-(4-Benzyloxy-benzylsulfanyl)-indan-4-yloxy]-acetic acid (compound 69)The title compound was prepared in the manner analogous to Example 1using 69A. mp 145-147° C.; IR (KBr) cm⁻¹: 3066, 2584, 1742, 1511, 1234;400 MHz ¹H NMR (DMSO-d₆): δ 12.94 (br(s), 1H), 7.21-7.44 (m, 5H),6.99-7.15 (m, 3H) 6.80-6.90 (m, 2H), 6.56 (d, 1H, J=8.3 Hz), 5.01 (s,2H), 4.61 (s, 2H), 3.93 (s, 2H), 2.75 (t, 2H, J=7.3 Hz), 2.67 (t, 2H,J=7.3 Hz), 1.89 (pentet, 2H); MS m/z 419 (M−1). Anal. Calc'd forC₂₅H₂₄O₄S: C, 71.40; H, 5.75; found: C, 71.46; H, 5.75.

EXAMPLE 70

Synthesis of{7-[4-(4-Chloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid(compound 70)

Step 1. Preparation of{7-[4(4Chloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acidmethyl ester (compound 70A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 1-(4-chloro-benzyloxy) 4chloromethyl benzene prepared from1-bromomethyl-4-chloro-benzene and 4-hydroxymethyl-phenol in the manneranalogous to Examples 14A and 14B. MS m/z 469 (M+1).Step 4. Preparation of{7-[4-(4-Chloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid(compound 70)The title compound was prepared in the manner analogous to Example 1using 70A. mp 170-172° C.; IR (KBr) cm⁻¹: 3054, 25.77, 1731, 1710, 1471,1234; 400 MHz ¹H NMR (DMSO-d₆): δ 12.95 (br(s), 1H), 7.39 (s, 4H),6.99-7.25 (m, 3H), 6.79-6.97 (m, 2H), 6.56 (d, 1H, J=8.4 Hz), 5.01 (s,2H), 4.60 (s, 2H), 3.93 (s, 2H), 2.74 (t, 2H, J=7.4 Hz), 2.66 (t, 2H,J=7.4 Hz), 1.88 (pentet, 2H); MS m/z 453 (M−1). Anal. Calc'd forC₂₅H₂₃ClO₄S: C, 66.00; H, 5.10; found: C, 65.95; H, 4.97.

EXAMPLE 71

Synthesis of{7-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 71)

Step 1. Preparation of{7-[4(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acidmethyl ester (compound 71A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 1,4-Dichloro-2-(4-chloromethyl-phenoxymethyl)-benzeneprepared from 1,4-dichloro-2-chloromethyl-benzene and4-hydroxymethyl-phenol in the manner analogous to Examples 14A and 14B.MS m/z 265 (M−237).Step 2. Preparation of{7-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 71)The title compound was prepared in the manner analogous to Example 1using 71A. mp 158-160° C.; IR (KBr) cm⁻¹: 3070, 2573, 1747, 1716, 1236,1106; 400 MHz ¹H NMR (DMSO-d₆): δ 12.95 (br(s), 1H), 7.57-7.62 (m, 1H),7.47-7.53 (m, 1H), 7.38-7.45 (m, 1H), 7.08-7.16 (m, 2H), 7.04 (d, 1H,J=8.5 Hz), 6.85-6.92 (m, 2H), 6.56 (d, 1H, J=8.5 Hz), 5.06 (s, 2H), 4.61(s, 2H), 3.94 (s, 2H), 2.75 (t, 2H, J=7.3 Hz), 2.67 (t, 2H, J=7.3 Hz),1.89 (pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C₂₅H₂₂Cl₂O₄S: C,61.35; H, 4.53; found: C, 61.24; H, 4.43.

EXAMPLE 72

Synthesis of{7-[4-(3,4-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 72)

Step 1. Preparation of{7-[4(3,4Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acidmethyl ester (compound 72A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 1,2-Dichloro-4-(4-chloromethyl-phenoxymethyl)-benzeneprepared from 1-bromomethyl-3,4-dichloro-benzene and4-hydroxymethyl-phenol in the manner analogous to Examples 14A and 14B.MS m/z 503 (M+1).Step 2. Preparation of{7-[4-(3,4Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid(compound 72)The title compound was prepared in the manner analogous to Example 1using 72A. mp 168° C.; IR (KBr) cm⁻¹: 3084, 3039, 1744, 1708, 1244,1226; 400 MHz ¹H NMR (DMSO-d₆): δ 12.95 (br(s), 1H), 7.57-7.67 (m, 2H),7.37 (dd, 1H, J=8.3, 2.0 Hz), 7.01-7.14 (m, 3H), 6.82-6.89 (m, 2H), 6.56(d, 1H, J=8.4 Hz), 5.04 (s, 2H), 4.61 (s, 2H), 3.93 (s, 2H), 2.75 (t,2H, J=7.4 Hz), 2.66 (t, 2H, J=7.4 Hz), 1.88 (pentet, 2H); MS m/z 487(M−1). Anal. Calc'd for C₂₅H₂₂Cl₂O₄S: C, 61.35; H, 4.53; found: C,61.13; H, 4.38.

EXAMPLE 73

Synthesis of{7-[4-(4Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 73)

Step 1. Preparation of{7-[4-(4-Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 73A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and1-Chloro-4-(4-chloromethyl-phenoxymethyl)-2-trifluoromethyl-benzeneprepared from 1-bromomethyl-4-chloro-3-trifluoromethyl-benzene and4-hydroxymethyl-phenol in the manner analogous to Examples 14A and 14B.MS m/z 299 (M−237).Step 2. Preparation of{7-[4-(4-Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 73)The title compound was prepared in the manner analogous to Example 1using 73A. mp 151-152° C.; IR (KBr) cm⁻¹: 3076, 3050, 1748, 1426, 1244,1109; 400 MHz ¹H NMR (DMSO-d₆): δ 12.94 (br(s), 1H), 7.87 (s, 1H),7.68-7.72 (m, 2H) 7.00-7.15 (m, 3H), 6.82-6.92 (m, 2H), 6.56 (d, 1H,J=8.5 Hz), 5.12 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.74 (t, 2H, J=7.5Hz), 2.66 (t, 2H, J=7.5 Hz), 1.87 (pentet, 2H); MS m/z 521 (M−1). Anal.Calc'd for C26H₂₂ClF₃O₄S: C, 59.71; H, 4.24; found: C, 59.54; H, 4.11.

EXAMPLE 74

Synthesis of{7-[4-(4-Fluoro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 74)

Step 1. Preparation of{7-[4-(4-Fluoro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 74A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and4-(4-Chloromethyl-phenoxymethyl)-1-fluoro-2-trifluoromethyl-benzeneprepared from 1-bromomethyl-4-fluoro-3-trifluoromethyl-benzene and4-hydroxymethyl-phenol in the manner analogous to Examples 14A and 14B.MS m/z 283 (M−237).Step 2. Preparation of{7-[4-(4-Fluoro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 74)The title compound was prepared in the manner analogous to Example 1using 74A. mp 116-117° C.; IR (KBr) cm⁻¹: 3028, 1741, 1704, 1511, 1235,1110; 400 MHz ¹H NMR (DMSO-d₆): δ 12.96 (br(s), 1H), 7.74-7.85 (m, 2H),7.45-7.54 (m, 1H), 7.08-7.15 (m, 2H), 7.04 (d, 1H, J=8.5 Hz), 6.84-6.91(m, 2H), 6.56 (d, 1H, J=8.5 Hz), 5.09 (s, 2H), 4.61 (s, 2H), 3.94 (s,2H), 2.75 (t, 2H, J=7.5 Hz), 2.66 (t, 2H, J=7.5 Hz), 1.88 (pentet, 2H);MS m/z 505 (M−1). Anal. Calc'd for C₂₆H₂₂F₄O₄S: C, 61.65; H, 4.38;found: C, 61.50; H, 4.07.

EXAMPLE 75

Synthesis of{7-[4-(4-Trifluoromethoxy-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 75)

Step 1. Preparation of[7-(4-Acetoxy-benzylsulfanyl)-indan-4-yloxy]-acetic acid methyl ester(compound 75A)

The title compound was prepared in the manner analogous to Example 35Ausing acetic acid 4-chloromethyl-phenyl ester and 12C. MS m/z 387 (M+1).Step 2. Preparation of[7-(4-Hydroxy-benzylsulfanyl)-indan-4-yloxy]-acetic acid (compound 75B)

The title compound was prepared in the manner analogous to Example 35Busing 75A. MS m/z 391 (M−1).Step 3. Preparation of[7-(4-Hydroxy-benzylsulfanyl)-indan-4-yloxy]-acetic acid methyl ester(compound 75C)

The title compound was prepared in the manner analogous to Example 35Cusing the product from Example 75B. MS m/z 237 (M−107).Step 4. Preparation of{7-[4-(4-Trifluoromethoxy-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 75D)

The title compound was prepared in the manner analogous to Example 1Fusing 1-bromomethyl-4-trifluoromethoxy-benzene and 75C. MS m/z 519(M+1).Step 5. Preparation of{7-[4-(4-Trifluoromethoxy-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 75)The title compound was prepared in the manner analogous to Example 1using 75D. mp 140-142° C.; IR (KBr) cm⁻¹: 3072, 3043, 1724, 1511, 1226,1156; 400 MHz ¹H NMR (DMSO-d₆): δ 12.95 (br(s), 1H), 7.47-7.57 (m, 2H),7.29-7.39 (m, 2H), 7.00-7.16 (m, 3H), 6.81-6.91 (m, 2H), 6.56 (d, 1H,J=8.5 Hz), 5.05 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.75 (t, 2H, J=7.4Hz), 2.67 (t, 2H, J=7.4 Hz), 1.88 (pentet, 2H) MS m/z 503 (M−1). Anal.Calc'd for C₂₆H₂₃F₃O₃S: C, 61.90; H, 4.60; found: C, 61.53; H, 4.36.

EXAMPLE 76

Synthesis of{7-[4-(4-Fluoro-2-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 76)

Step 1. Preparation of{7-[4-(4-Fuoro-2-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 76A)

The title compound was prepared in the manner analogous to Example 1Fusing 1-bromomethyl-fluoro-2-trifluoromethyl-benzene and the productprepared from Example 75C. MS m/z 283Step 2. Preparation of{7-[4-(4-Fluoro-2-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 76)The title compound was prepared in the manner analogous to Example 1using 76A. mp 125-127° C.; IR (KBr) cm⁻¹: 3132, 3032, 1742, 1708, 1244,1110; 400 MHz ¹H NMR (DMSO-d₆): δ 12.95 (br(s), 1H), 7.71-7.81 (m, 1H),7.65 (dd, 1H, J=9.3, 2.6 Hz), 7.51-7.61 (m, 1H), 7.01-7.19 (m, 3H),6.81-6.91 (m, 2H), 6.57 (d, 1H, J=8.5 Hz), 5.11 (s, 2H), 4.61 (s, 2H),3.95 (s, 2H), 2.75 (t, 2H, J=7.4 Hz), 2.66 (t, 2H, J=7.4 Hz), 1.89(pentet, 2H); MS m/z 502 (M−1). Anal. Calc'd for C₂₆H₂₂F₄O₄S: C, 61.65;H, 4.38; found: C, 61.28; H, 4.12.

EXAMPLE 77

Synthesis of{7-[4-(3,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 77)

Step 1. Preparation of{7-[4(3,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acidmethyl ester (compound 77A)

The product from Example 75C (0.42 g, 1 mmoles),(3,5-dichlorophenyl)-methanol (0.24 g, 1.3 mmoles), triphenyl phosphine(0.38 g, 1.5 mmoles) and 0.23 mL of diethyl azodicarboxylate (0.25 g,1.5 mmoles) were dissolved in 9 mL of tetrahydrofuran. The reactionmixture was stirred at room temperature under nitrogen for 18 hrs. Thereaction mixture was evaporated to give a residue, which was flashchromatographed (silica gel, 20% ethyl acetate in hexane) to afford thetitle compound in good purity. MS m/z 265Step 2. Preparation of{7-[4-(3,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 77)The title compound was prepared in the manner analogous to Example 1using 77A. mp 134-135° C.; IR (KBr) cm⁻¹: 3070, 1747, 1708, 1572, 1432,1244; 400 MHz ¹H NMR (DMSO-d₆): δ 12.95 (br(s), 1H), 7.51-7.53 (m, 1H),7.42-7.45 (m, 2H), 7.07-7.13 (m, 2H), 7.04 (d, 1H, J=8.6 Hz), 6.83-6.90(m, 2H), 6.56 (d, 1H, J=8.6 Hz), 5.05 (s, 2H), 4.61 (s, 2H), 3.93 (s,2H), 2.75 (t, 2H, J=7.5 Hz), 2.66 (t, 2H, 7.5 Hz), 1.88 (pentet, 2H); MSm/z 487 (M−1). Anal. Calc'd for C₂₅H₂₂Cl₂O₄S: C, 61.35; H, 4.53; found:C, 61.01; H, 436.

EXAMPLE 78

Synthesis of{7-[4-Methoxy-3-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 78)

Step 1. Preparation of[4-Methoxy-3-(4-trifluoromethyl-benzyloxy)-phenyl]-methanol (compound78A)

The title compound was prepared in the manner analogous to Example 14Ausing 1-bromomethyl-4-trifluoromethyl-benzene and5-hydroxymethyl-2-methoxy-phenol. MS m/z 295 (M-OH).Step 2. Preparation of4-Chloromethyl-1-methoxy-2-(4-trifluoromethyl-benzyloxy)-benzene(compound 78B)

The title compound was prepared in the manner analogous to Example 3Busing 78A. MS m/z 295 (M-Cl).Step 3. Preparation of{7-[4-Methoxy-3-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 78C)

The title compound was prepared in the manner analogous to Example 1Fusing 78B and 12C. MS m/z 373 (M−159).Step 4. Preparation of{7-[4-Methoxy-3-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 78)The title compound was prepared in the manner analogous to Example 1using 78C. mp 150-151° C.; IR (KBr) cm⁻¹: 3046, 1722, 1515, 1328, 1232,1106; 400 MHz ¹H NMR (DMSO-d₆): δ 12.95 (br(s), 1H), 7.71 (d, 2H, J=8.1Hz), 7.58 (d, 2H, J=8.1 Hz), 7.03 (d, 1H, J=8.5 Hz), 6.70-6.86 (m, 3H),6.57 (d, 1H, J=8.5 Hz), 5.01 (s, 2H), 4.61 (s, 2H), 3.89 (s, 2H), 3.69(s, 3H), 2.75 (t, 2H, J=7.3 Hz), 2.62 (t, 2H, J=7.3 Hz), 1.87 (pentet,2H); MS m/z 517 (M−1). Anal. Calc'd for C₂₇ H₂₅F₃O₃S: C, 62.54; H, 4.86;found: C, 62.54; H, 4.71.

EXAMPLE 79

Synthesis of{7-[3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 79)

Step 1. Preparation of [3-(4-trifluoromethyl-benzyloxy)-phenyl]-methanol(compound 79A)

The title compound was prepared in the manner analogous to Example 14Ausing 1-bromomethyl-4-trifluoromethyl-benzene and3-hydroxymethyl-phenol. MS m/z 265(M-OH).Step 2. Preparation of1-(4-trifluoromethyl-benzyloxy)-3-chloromethyl-benzene (compound 79B)

The title compound was prepared in the manner analogous to Example 3Busing 79A. MS m/z 265 (M-Cl).Step 3. Preparation of{7-[3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 79C)

The title compound was prepared in the manner analogous to Example 1Fusing 79B and 12C. MS m/z 503 (M+1).Step 4. Preparation of{7-[3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 79)The title compound was prepared in the manner analogous to Example 1using 79C. mp 145-146° C.; IR (KBr) cm⁻¹: 3076, 3028, 1705, 1318, 1232,1109; 400 MHz ¹H NMR (DMSO-d₆): δ 12.94 (br(s), 1H), 7.71 (d, 2H, J=8.2Hz), 7.59 (d, 2H, J=8.0 Hz), 7.10-7.19 (m, 1H), 7.05 (d, 1H, J=8.5 Hz),6.75-6.86 (m, 4H), 6.58 (d, 1H, J=8.5 Hz), 5.08 (s, 2H), 4.61 (s, 2H),3.95 (s, 2H), 2.75 (t, 2H, J=7.5 Hz), 2.64 (t, 2H, J=7.5 Hz), 1.88(pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C₂₆H₂₃F₃O₄S: C, 63.92;H, 4.75; found: C, 63.78; H, 4.53.

EXAMPLE 80

Synthesis of{7-[3-(4-Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 80)

Step 1. Preparation of[3-(4Chloro-3-trifluoromethyl-benzyloxy)-phenyl]-methanol (compound 80A)

The title compound was prepared in the manner analogous to Example 14Ausing 4-bromomethyl-1chloro-2-trifluoromethyl-benzene and3-hydroxymethyl-phenol. MS m/z 299 (M-OH).Step 2. Preparation of1-Chloro-4-(3-chloromethyl-phenoxymethyl)-2-trifluoromethyl-benzene(compound 80B)

The title compound was prepared in the manner analogous to Example 3Busing 80A. MS m/z 299 (M-Cl).Step 3. Preparation of{7-[3-(4-Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 80C)

The title compound was prepared in the manner analogous to Example 1Fusing 80B and 12C. MS m/z 537 (M+1).Step 4. Preparation of{7-[3-(4-Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 80)The title compound was prepared in the manner analogous to Example 1using 80C. mp 121-122° C.; IR (KBr) cm⁻¹: 3027, 2584, 1742, 1255, 1129,1109; 400 MHz ¹H NMR (DMSO-d₆): δ 12.95 (br(s), 1H), 7.87 (s, 1H),7.64-7.75 (m, 2H), 7.09-7.19 (m, 1H), 7.01-7.09 (m, 1H), 6.73-6.88 (m,3H), 6.56 (d, 1H, J=8.5 Hz), 5.06 (s, 2H), 4.60 (s, 2H), 3.95 (s, 2H),2.74 (t, 2H, J=7.4 Hz), 2.63 (t, 2H, J=7.4 Hz), 1.87 (pentet, 2H); MSm/z 523 (M+1). Anal. Calc'd for C₂₆H₂₂ClF₃O₄S: C, 59.71; H, 4.24; found:C, 59.45; H, 4.08.

EXAMPLE 81

Synthesis of{7-[2-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 81)

Step 1. Preparation of [2-(4-Trifluoromethyl-benzyloxy)-phenyl]-methanol(compound 81A)

The title compound was prepared in the manner analogous to Example 14Ausing 1-bromomethyl-4-trifluoromethyl-benzene and2-hydroxymethyl-phenol. MS m/z 265 (M-OH).Step 2. Preparation of1-(4-trifluoromethyl-benzyloxy)-2-chloromethyl-benzene (compound 81B)

The title compound was prepared in the manner analogous to Example 3Busing 81A. MS m/z 265 (M-Cl).Step 3. Preparation of{7-[2-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 81C)

The title compound was prepared in the manner analogous to Example 1Fusing 81B and 12C. MS m/z 503 (M+1).Step 4. Preparation of{7-[2-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 81)The title compound was prepared in the manner analogous to Example 1using 81C. mp 150-152° C.; IR (KBr) cm⁻¹: 3074, 3042, 1701, 1324, 1124,1099; 400 MHz ¹H NMR (DMSO-d₆): δ 7.58-7.75 (m, 2H), 6.92-7.20 (m, 4H),6.80 (t, 1H, J=7.5 Hz), 6.51 (d, 1H, J=8.5 Hz), 5.16 (s, 2H), 4.57 (s,2H), 3.99 (s, 2H), 2.70 (t, 2H, J=7.5 Hz), 2.62 (t, 2H, J=7.5 Hz), 1.80(pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C₂₆H₂₃F₃O₄S: C, 63.92;H, 4.75; found: C, 63.54; H, 4.52.

EXAMPLE 82

Synthesis of{7-[3-Dichloro-4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid lithium salt (compound 82)

Step 1. Preparation of[3,5-Dichloro-(4-trifluoromethyl-benzyloxy)-phenyl]-methanol (compound82A)

The title compound was prepared in the manner analogous to Example 14Ausing 1-bromomethyl-4-trifluoromethyl-benzene and2,6-dichloro-4-hydroxymethyl-phenol. MS m/z 191 (M−159).Step 2. Preparation of1,3-Dichloro-5-chloromethyl-2-(4-trifluoromethyl-benzyloxy)-benzene(compound 82B)

The title compound was prepared in the manner analogous to Example 3Busing 82A. MS m/z 333 (M-Cl).Step 3. Preparation of{7-[3,5-Dichloro-4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 82C)

The title compound was prepared in the manner analogous to Example 1Fusing 82B and 12C. MS m/z 571 (M+1).Step 4. Preparation of The Lithium Salt of{7-[3,5-Dichloro-4(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-aceticacid (compound 82)The title compound, in unprotonated form, was prepared in the manneranalogous to Example 1 using 82C. mp 235° C. dec; IR (KBr) cm⁻¹: 3414,1622, 1591, 1472, 1326, 1265; 400 MHz ¹H NMR (DMSO-d₆): δ 7.66-7.77 (m,4H), 7.26 (s, 2H), 6.99 (d, 1H, J=8.5 Hz), 6.45 (d, 1H, J=8.5 Hz), 5.03(s, 2H), 4.02 (s, 2H), 3.92 (s, 2H), 2.73 (t, 2H, J=7.3 Hz), 2.65 (t,2H, J=7.3 Hz), 1.88 (pentet, 2H); MS m/z 555 (M−1). Anal. Calc'd forC₂₆H₂₀Cl₂F₃O₄S; Li: 0.50 H₂O: C, 54.56; H, 3.70; Li, 1.21; H₂O, 1.57;found: C, 54.63; H, 3.68; Li, 1.46; H₂O, 1.61.

EXAMPLE 83

Synthesis of{8-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 83)

Step 1. Preparation of{8-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid methyl ester (compound 83A)

The title compound was prepared in the manner analogous to Example 1Fusing (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester and 14B. MSm/z 519 (M+1).Step 2. Preparation of{8-[4(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 83)The title compound was prepared in the manner analogous to Example 1using 83A. mp 143-144° C.; HPLC: area %=96.02, r.t.=3.770 min, γ=214 nm,mobile phase=acetonitrile/water w/0.10% TFA; IR (KBr) cm⁻¹: 3042, 2581,1739, 1714, 1325, 1116; 400 MHz ¹H NMR (DMSO-d₆): δ 12.95 (br(s), 1H),7.66-7.74 (m, 2H), 7.56-7.63 (m, 2H), 7.10-7.17 (m, 2H), 6.92 (d, 1H,J=8.7 Hz), 6.83-6.89 (m, 2H), 6.26 (d, 1H, J=8.5 Hz), 5.13 (s, 2H), 4.58(s, 2H), 4.08 (t, 2H, J=4.8 Hz), 3.90 (s, 2H), 2.55 (t, 2H, J=6.5 Hz),1.83 (pentet, 2H); MS m/z 503 (M−1). Anal. Calc'd for C₂₆H₂₃F₃O₅S: C,61.90; H, 4.60; found: C, 61.41; H, 4.50.

EXAMPLE 84

Synthesis of{8-[3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 84)

Step 1. Preparation of{8-[3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid methyl ester (compound 84A)

The title compound was prepared in the manner analogous to Example 1Fusing (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester and 79B. MSm/z 519 (M+1).Step 2. Preparation of{8-[3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 84)The title compound was prepared in the manner analogous to Example 1using 84A. mp 113-115° C.; HPLC: area %=97.30, r.t.=3.140 min, γ=214 nm,mobile phase=acetonitrile/water w/0.10% TFA; IR (KBr) cm⁻: 2952, 2577,1742, 1582, 1323, 1120; 400 MHz ¹H NMR (DMSO-d₆): δ 7.67-7.74 (m, 2H),7.56-7.63 (m, 2H), 7.13 (t, 1H, J=7.8 Hz), 6.76-6.93 (m, 4H), 6.22 (d,1H, J=8.7 Hz), 5.08 (s, 2H), 4.45 (s, 2H), 4.08 (t, 2H, J=4.8 Hz), 3.91(s, 2H), 2.54 (t, 2H, J=6.6 Hz), 1.82 (pentet, 2H); MS m/z 505 (M+1).Anal. Calc'd for C₂₆H₂₃F₃O₅S: C, 61.90; H, 4.60; found: C, 61.49; H,4.44.

EXAMPLE 85

Synthesis of{8-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 85)

Step 1. Preparation of{8-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid methyl ester (compound 85A)

The title compound was prepared in the manner analogous to Example 1Fusing (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester and1,4-Dichloro-2-(4-chloromethyl-phenoxymethyl)-benzene prepared in themanner analogous to Example 71A. MS m/z 519 (M+1).Step 2. Preparation of{8-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 85)The title compound was prepared in the manner analogous to Example 1using 85A. mp 98-100° C.; IR (KBr) cm⁻¹: 3038, 2854, 1729, 1508, 1240,1124; 400 MHz ¹H NMR (MSOd-₆): δ 12.95 (br(s), 1H), 7.57-7.62 (m, 1H),7.39-7.53 (m, 2H), 7.12-7.20 (m, 2H), 6.84-6.96 (m, 3H), 6.26 (d, 1H,J=8.6 Hz), 5.05 (s, 2H), 4.58 (s, 2H), 4.09 (t, 2H, J=4.9 Hz), 3.92 (s,2H), 2.55 (t, 2H, J=6.5 Hz), 1.83 (pentet, 2H); MS m/z 503 (M−1). Anal.Calc'd for C₂₅H₂₂Cl₂O₅S: C, 59.41; H, 4.39; found: C, 59.20; H, 4.20.

EXAMPLE 86

Synthesis of{8-[4-(5-Trifluoromethyl-pyridine-2-yl)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 86)

Step 1.{8-[4-(5-Trifluoromethyl-pyridine-2-yl)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid methyl ester (compound 86A)

The title compound was prepared in the manner analogous to Example 1Fusing (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester and 18B. MSm/z 490 (M+1).Step 2.{8-[4-(5-Trifluoromethyl-pyridine-2-yl)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 86)The title compound was prepared in the manner analogous to Example 1using 86A. mp 178-179° C.; IR (KBr) cm⁻¹: 3034, 2577, 1707, 1604, 1332,1111; 400 MHz ¹H NMR (DMSO-d₆): δ 12.95 (br(s), 1H), 8.97 (s, 1H),7.99-8.24 (m, 4H), 7.33-7.40 (m, 2H), 6.95 (d, 2H, J=8.5 Hz), 6.26 (d,2H, J=8.6 Hz), 4.57 (s, 2H), 4.11 (t, 2H, J=4.9 Hz), 4.04 (s, 2H), 2.56(t, 2H, J=6.5 Hz), 1.84 (pentet, 2H); MS m/z 476 (M+1). Anal. Calc'd forC₂₄H₂₀F₃NO₄S: C, 60.63; H, 4.24; N, 2.95; found: C, 60.31; H, 4.24; N,3.02.

EXAMPLE 87

Synthesis of{7-[5-(2-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 87)

Step 1. Preparation of{7-[5-(2-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 87A)

The title compound was prepared in the manner analogous to Example 1Fusing commercially available 3-chloromethyl-5-(2-chloro-phenyl)isoxazoleand 12C. MS m/z 430 (M+1).Step 2. Preparation of{7-[5-(2-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 87)The title compound was prepared in the manner analogous to Example 1using 87A. mp 161-162° C.; IR (KBr) cm⁻¹: 3177, 3065, 1706, 1475, 1432,1233; 400 MHz ¹H NMR (DMSO-d₆): δ 13.00 (bs, 1H), 7.78-7.85 (m, 1H),7.58-7.64 (m, 1H), 7.42-7.53 (m, 2H), 7.15 (d, 1H, J=8.6 Hz), 6.84 (s,1H), 6.60 (d, 1H, J=8.6 Hz), 4.62 (s, 2H), 4.09 (s, 2H), 2.72-2.82 (m,4H), 1.91 (pentet, 2H); MS m/z 416 (M+1). Anal. Calc'd for C₂₁H₁₈ClNO₄S:C, 60.65; H, 4.36; N, 3.37; found: C, 60.56; H, 4.28; N, 3.16.

EXAMPLE 88

Synthesis of{7-[3-(2,6-Dichloro-phenyl)-5-methyl-isoxazol-4-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 88)

Step 1. Preparation of{7-[3-(2,6-Dichloro-phenyl)-5-methyl-isoxazol-4-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 88A)

The title compound was prepared in the manner analogous to Example 1Fusing commercially available4-bromomethyl-3-(2,6-dichloro-phenyl)-5-methyl-isoxazole and 12C. MS m/z478 (M+1).Step 2. Preparation of{7-[3-(2,6-Dichloro-phenyl)-5-methyl-isoxazol-4-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 88)The title compound was prepared in the manner analogous to Example 1using 88A. mp 151-152° C.; IR (KBr) cm⁻¹: 3084, 1743, 1430, 1277, 1245,1106; 400 MHz ¹H NMR (DMSO-d₆): δ 12.97 (br(s), 1H), 7.47-7.70 (m, 3H),6.90 (d, 1H, J=8.5 Hz), 6.52 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 3.58 (s,2H), 2.75 (t, 2H, J=7.6 Hz), 2.65 (t, 2H, J=7.6 Hz), 2.07 (s, 3H), 1.89(pentet, 2H) MS m/z 464 (M+1). Anal. Calc'd for C₂₂H₁₉Cl₂NO₄S: C, 56.90;H, 4.12; N, 3.02; found: C, 56.51; H, 3.96; N, 2.95.

EXAMPLE 89

Synthesis of{7-[3-(4-Trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 89)

Step 1. Preparation of{7-[3-(4-Trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 89A)

The title compound was prepared in the manner analogous to Example 1Fusing 42C and 12C. MS m/z 464 (M+1).Step 2. Preparation of{7-[3-(4-Trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 89)The title compound was prepared in the manner analogous to Example 1using 89A. mp 166-168° C.; HPLC: area %=96.95; r.t.=3.140 min, γ=214 nm,mobile phase=acetonitrile/water w/0.10% TFA. IR (KBr) cm⁻¹: 3140, 3085,1742, 1322, 1255, 1109; 400 MHz ¹H NMR (DMSO-d₆): δ 12.96 (br(s), 1H),7.99 (d, 2H, J=8.3 Hz), 7.81 (d, 2H, J=8.3 Hz), 7.14 (d, 1H, J=8.4 Hz),6.81 (s, 1H), 6.61 (d, 1H, J=8.4 Hz), 4.63 (s, 2H), 4.23 (s, 2H), 2.76(t, 4H, J=7.5 Hz), 1.91 (pentet, 2H); MS m/z 450 (M+1). Anal. Calc'd forC₂₂H₁₈F₃NO₄S: C, 58.79; H, 4.04; N, 3.12; found: C, 58.38; H, 3.92; N,2.95.

EXAMPLE 90

Synthesis of{7-[2-(4′-Trifluoromethyl-biphenyl-4yl)-ethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 90)

Step 1. Preparation of{7-[2-(4′-Trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 90A)

The title compound was prepared in the manner analogous to Example 1Fusing 12C and 4-(2-bromo-ethyl)-4′-trifluoromethyl-biphenyl (compound22B). MS m/z 487 (M+1).Step 2. Preparation of{7-[2-(4′-Trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 90)The title compound was prepared in the manner analogous to Example 1using 90A. mp 170-172° C.; IR (thin film) cm⁻¹: 1724, 1471, 1327, 1239,1175, 1110; 400 MHz ¹H NMR (DMSO-d₆) δ 12.96 (br s, 1H), 7.82 (d, 2H,J=8.3 Hz), 7.74 (d, 2H, J=8.3 Hz), 7.61 (d, 2H, J=8.3 Hz), 7.31 (d, 2H,J=8.3 Hz), 7.12 (d, 2H, J=8.5 Hz), 6.62 (d, 1H, J=8.5 Hz), 4.63 (s, 2H),3.08 (t, 2H, J=7.6 Hz), 2.80 (m, 6H), 1.96 (m, 2H); MS m/z 471 (M−1).Anal. Calc'd for C₂₆H₂₃F₃O₃S: C, 66.09; H, 4.91; found: C, 65.95; H,4.63.

EXAMPLE 91

Synthesis of{7-[2-(4′-Trifluoromethyl-biphenyl-4-yl)-ethyl]-indan-4-yloxy}-aceticacid (compound 91)

Step 1. Preparation of (Indan-4-yloxy)-acetic acid methyl ester(compound 91A)

Compound 91A was prepared from indan-4-ol and bromo-acetic acid methylester in the manner analogous to Example 1C. 400 MHz ¹H NMR (DMSO-d₆) δ7.00 (t, 1H, J=7.8 Hz), 6.79 (d, 1H, J=7.3 Hz), 6.56 (d, 1H, J=8.1 Hz),4.74 (s, 2H), 3.63 (s, 3H), 2.77 (m, 4H), 1.95 (m, 2H).Step 2. Preparation of (4′-Trifluoromethyl-biphenyl-4-yl)-acetic acid(compound 91B)

A mixture of (4-bromo-phenyl)-acetic acid (10.2 g, 47.4 mmol),4-trifluoromethylphenylboronic acid (10.0 g, 52.7 mmol), and 50%water-wet 5% palladium on charcoal catalyst (4.6 g) in 50 ml of waterand 8.0 ml of 2-propanol was treated dropwise over 30 minutes with asolution of sodium carbonate (6.8 g, 64.2 mmol) in 18 ml of water. Themixture was heated at 65-70° C. for 3 h, then cooled to 40° C. andtreated with 13.0 ml of a solution of 2-propanol/water/2.0 N aqueoussodium hydroxide solution (70/15/1). The reaction mixture was filteredthrough a bed of Celite filter-aid, and the filter cake was washed 5×with the above 2-propanol/water/2.0 N aqueous sodium hydroxide solution.The combined filtrates were diluted with 125 ml of water, and thesolution was digested on the steam bath with charcoal and filtered. Thefiltrate was diluted with an additional 150 ml of water and madestrongly acidic by the addition of 4.0 N hydrochloric acid. Theprecipitated product was filtered and suspended in 350 ml of water plus50 ml of methanol. The new mixture was stirred for several hours andfiltered again. The crude product was recrystallized from aqueousacetonitrile. A sample recrystallized a second time from aqueousacetonitrile had mp 158-160° C.; MS m/z 280 (M).Step 3. Preparation of (4′-Trifluoromethyl-biphenyl-4-yl)-acetylchloride (compound 91C)

A suspension 91B (2.0 g, 7.1 mmol) and 5 drops of N,N-dimethylformamidein 30 ml of dichloromethane was cooled in ice and treated dropwise witha solution of oxalyl chloride (0.70 ml, 1.0 g, 8.0 mmol) in 10 ml ofdichloromethane. The ice bath was removed, and the mixture was stirredat room temperature for 3 h. The solution was filtered, and the filtratewas evaporated. The residue quickly crystallized to yield the acidchloride intermediate, which was used immediately in the next step.Step 4. Preparation of{7-[2-(4′-Trifluoromethyl-biphenyl-4-yl-acetyl]-indan-4-yloxy}-aceticacid methyl ester (compound 91D)

A solution of 91C (2.1 g, 7.0 mmol) in 25 ml of 1,2-dichloro-ethane wascooled in ice and treated with anhydrous ferric chloride (1.2 g, 7.4mmol). The mixture was stirred, and a solution of 91A (1.5 g, 7.3 mmol)in 10 ml of 1,2-dichloro-ethane was added dropwise. The mixture wasstirred at room temperature for 18 h. The reaction mixture was added to300 g of ice and of brine and extracted with ethyl acetate (4×100 ml).The combined extracts were washed with 5% aqueous sodium bicarbonatesolution (4×250 ml) and brine (1×250 ml), then dried over anhydroussodium sulfate and concentrated. The crude product was purified bynormal phase chromatography. A sample recrystallized from ethylacetate/hexane had mp 141-143° C.; MS m/z 467 (M−1).Step 5. Preparation of{7-[2-(4′-Trifluoromethyl-biphenyl-4-yl)-ethyl]-indan-4-yloxy}-aceticacid methyl ester (compound 91E)

A solution of 91D (1.0 g, 2.1 mmol) in 10.0 ml of trifluoroacetic acidwas treated dropwise with triethylsilane (1.5 ml, 1.1 g, 9.4 mmol). Themixture was stirred at room temperature for 3 h and then added to 200 gof ice and water. The precipitated solid was extracted out with ethylacetate (4×100 ml). The combined extracts were washed with brine (1×250ml), 5% aqueous sodium bicarbonate solution (4×250 ml), and brine again,then dried over anhydrous sodium sulfate and concentrated. The crudeproduct was purified by normal phase chromatography. 400 MHz ¹H NMR(DMSO-d₆) δ 7.82 (d, 2H, J=8.3 Hz), 7.75 (d, 2H, J=8.3 Hz), 7.61 (d, 2H,J=8.3 Hz), 7.30 (d, 2H, J=8.3 Hz), 6.90 (d, 1H, J=8.3 Hz), 6.53 (d, 1H,J=8.3 Hz), 4.71 (s, 2H), 3.63 (s, 2H), 2.77 (m, 8H), 1.94 (m, 2H).Step 6. Preparation of{7-[2-(4′-Trifluoromethyl-biphenyl-4-yl)-ethyl]-indan-4-yloxy}-aceticacid (compound 91)The title compound was prepared in the manner analogous to Example 1using 91E. mp 188-190° C.; IR (thin film) cm⁻¹: 1745, 1322, 1252, 1170,1112, 1071; 400 MHz ¹H NMR (DMSO-d₆) δ 12.89 (br s, 1H), 7.83 (d, 2H,J=8.1 Hz), 7.74 (d, 2H, J=8.5 Hz), 7.61 (d, 2H, J=8.1 Hz), 7.30 (d, 2H,J=8.3 Hz), 6.90 (d, 1H, J=8.3 Hz), 6.51 (d, 1H, J=8.3 Hz), 4.58 (s, 2H),2.75(m, 8H), 2.45 (m, 2H); MS m/z 439 (M−1). Anal. Calc'd forC₂₆H₂₃F₃O₃: C, 70.90; H, 5.26; found: C, 70.92; H, 5.01.

EXAMPLE 92

Synthesis of{5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-2,3-dihydro-benzofuran-4-yloxy}-aceticacid (compound 92)

Step 1. Preparation of{5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-2,3-dihydro-benzofuran-4-yloxy}-aceticacid methyl ester (compound 92A)

The title compound was prepared in the manner analogous to Example 1Fusing 18B and 7-mercapto-5-methyl-2,3-dihydro-benzofuran-4-yloxy)-aceticacid methyl ester (prepared in a similar manner as described for Example12C). mp 94-95° C.; MS m/z 490 (M+1).Step 2. Preparation of(5-Methyl-7-[4(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-2,3-dihydro-benzofuran-4-yloxy)-aceticacid (compound 92)The title compound was prepared in the manner analogous to Example 1using 92A. mp 155-157° C.; IR (thin film) cm⁻¹: 1732, 1587, 1416, 1331,1211, 1129; 400 MHz ¹H NMR (DMSO-d₆) δ 12.89 (br s, 1H), 8.97 (m, 1H),8.21 (dd, 1H, J=2.0, 8.5 Hz), 8.12 (d, 1H, J=8.3 Hz), 8.02 (d, 2H, J=8.3Hz), 7.34 (d, 2H, J=8.5 Hz), 6.83 (s, 1H), 4.56 (s, 2H), 4.48 (t, 2H,J=8.7 Hz), 4.08 (s, 2H), 3.24 (t, 2H, J=8.7 Hz), 2.02 (s, 3H); MS m/z474 (M−1). Anal. Calc'd for C₂₄H₂₀F₃NO₄S: C, 60.63; H, 4.24; N, 2.95;found: C, 60.54; H, 4.19; N, 2.94.

EXAMPLE 93

Synthesis of[8-(4′-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-chroman-5-yloxy]-aceticacid (compound 93)

Step 1. Preparation of[8-(4′-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-chroman-5-yloxy]-aceticacid methyl ester (compound 93A)

The title compound was prepared in the manner analogous to Example 1Fusing 18B and (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester mp122-124° C.; MS m/z 489 (M+1).Step 2. Preparation of[8-(4′-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-chroman-5-yloxy]-aceticacid (compound 93)The title compound was prepared in the manner analogous to Example 1using 93A. mp 170-172° C.; IR (thin film) cm⁻¹: 1717, 1584, 1473, 1330,1231, 1118; 400 MHz ¹H NMR (DMSO-d₆) δ 12.94 (br s, 1H), 7.82 (d, 2H,J=8.1 Hz), 7.74 (d, 2H, J=8.5 Hz), 7.60 (d, 2H, J=8.3 Hz), 7.34 (d, 2H,J=8.3 Hz), 6.96 (d, 2H, J=8.8 Hz), 6.28 (d, 2H, J=8.8 Hz), 4.58 (s, 2H),4.11 (t, 2H, J=5.0 Hz), 4.03 (s, 2H), 2.56 (t, 2H, J=6.5 Hz), 1.84 (m,2H); MS m/z 473 (M−1). Anal. Calc'd for C₂₅H₂₁F₃O₄S: C, 63.28; H, 4.46;found: C, 63.28; H, 4.26.

EXAMPLE 94

Synthesis of{8-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 94)

Step 1. Preparation of{8-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-chroman-5-yloxy}-aceticacid methyl ester (compound 94A)

The title compound was prepared in the manner analogous to Example 1Fusing 42C and (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester. mp112-113° C.; MS m/z 480 (M+1).Step 2. Preparation of{8-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 94)The title compound was prepared in the manner analogous to Example 1using 94A. The crude produce was recrystallized from ethylacetate/hexane to yield the final product. mp 171-173° C.; IR (thinfilm) cm⁻¹: 1722, 1432, 1322, 1232, 1103, 1065; 400 MHz ¹H NMR (DMSO-d₆)δ 12.94 (br s, 1H), 8.01 (d, 2H, J=8.1 Hz), 7.84 (d, 2H, J=8.3 Hz), 7.09(s, 1H), 7.03 (d, 1H, J=8.5 Hz), 6.29 (d, 1H, J=8.5 Hz), 4.59 (s, 2H),4.08 (t, 2H, J=5.0 Hz), 4.04 (s, 2H), 2.55 (t, 2H, J=6.5 Hz), 1.83 (m,2H); MS m/z 464 (M−1). Anal. Calc'd for C₂₂H₁₈F₃NO₅S; C, 56.77; H, 3.90;N, 3.01; found: C, 56.80; H, 3.58; N, 3.07.

EXAMPLE 95

Synthesis of{8-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 95)

Step 1. Preparation of{8-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-chroman-5-yloxy}-aceticacid methyl ester (compound 95A)

The title compound was prepared in the manner analogous to Example 1Fusing 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole and(8-mercapto-chroman-5-yloxy)-acetic acid methyl ester. mp 131-133° C.;MS m/z 446 (M+1).Step 2. Preparation of{8-[5-(4Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 95)The title compound was prepared in the manner analogous to Example 1using 95A. mp 181-183° C.; IR (thin film) cm⁻¹: 1723, 1612, 1479, 1428,1231, 1134; 400 MHz ¹H NMR (DMSO-d₆) δ 12.95 (br s, 1H), 7.82 (m, 2H),7.54 (m, 2H), 7.02 (d, 1H, J=8.8 Hz), 6.94 (s, 1H), 6.29 (d, 1H, J=8.5Hz), 4.59 (s, 2H), 4.08 (t, 2H, J=5.0 Hz), 4.01 (s, 2H), 2.55 (t, 2H,J=6.6 Hz), 1.83 (m, 2H); MS m/z 430 (M−1). Anal. Calc'd forC₂₁H₁₈ClNO₅S: C, 58.40; H, 4.20; N, 3.24; found: C, 58.30; H, 3.91; N,3.28.

EXAMPLE 96

Synthesis of{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid (compound 96)

Step 1. Preparation of{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid methyl ester (compound 96A)

The title compound was prepared in the manner analogous to Example 1Fusing 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole and 2C. mp 79-80° C.;MS m/z 404 (M+1).Step 2. Preparation of{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid (compound 96)The title compound was prepared in the manner analogous to Example 1using 96A. mp 152-153° C.; IR (thin film) cm⁻¹: 1724, 1495, 1433, 1309,1225, 1196; 400 MHz ¹H NMR (DMSO-d₆) δ 12.96 (br s, 1H), 7.82 (m, 2H),7.54 (m, 2H), 7.19 (d, 1H, J=1.5 Hz), 7.12 (dd, 1H, J=2.1, 8.4 Hz), 6.97(s, 1H), 6.72 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 4.11 (s, 2H), 2.09 (s,3H); MS m/z 388 (M−1). Anal. Calc'd for C₁₉H₁₆ClNO₄S: C, 58.54; H, 4.14;N, 3.59; found: C, 58.53; H, 4.08; N, 3.50.

EXAMPLE 97

Synthesis of{7-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 97)

Step 1. Preparation of{7-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 97A)

The title compound was prepared in the manner analogous to Example 1Fusing 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole and 12C. mp 112-114°C.; MS m/z 430 (M+1).Step 2. Preparation of{7-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 97)The title compound was prepared in the manner analogous to Example 1using 97A. mp 157-159° C.; IR (thin film) cm⁻¹: 1731, 1612, 1465, 1433,1231, 1110; 400 MHz ¹H NMR (DMSO-d₆) δ 7.81 (m, 2H), 7.54 (m, 2H), 7.10(d, 1H, J=8.3 Hz), 6.95 (s, 1H), 6.59 (d, 1H, J=8.5 Hz), 4.62 (s, 2H),4.06 (s, 2H), 2.77 (m, 4H), 1.92 (m, 2H); MS m/z 414 (M−1). Anal. Calc'dfor C₂₁H₁₈ClNO₄S: C, 60.65; H, 4.36; N, 3.37; found: C, 60.62; H, 4.10;N, 3.31.

EXAMPLE 98

Synthesis of{7-[3-(4-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid (compound 98)

Step 1. Preparation of{7-[3-(4-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-indan-4-yloxy}-aceticacid methyl ester (compound 98A)

The title compound was prepared in the manner analogous to Example 1Fusing 5-chloromethyl-3-(4-chloro-phenyl)-isoxazole and 12C. mp 92-94°C.; MS m/z 430 (M+1).Step 2. Preparation of{7-[3-(4-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-indan-4-yloxy}-aceticacidThe title compound was prepared in the manner analogous to Example 1using 98A. mp 158-160° C.; IR (thin film) cm⁻¹: 1741, 1574, 1476, 1429,1252, 1110; 400 MHz ¹H NMR (DMSO-d₆) δ 7.78 (m, 2H), 7.51 (m, 2H), 7.13(d, 1H, J=8.6 Hz), 6.72 (s, 1H), 6.60 (d, 1H, J=8.5 Hz), 4.62 (s, 2H),4.20 (s, 2H), 2.76 (m, 4H), 1.91 (m, 2H); MS m/z 414 (M−1). Anal. Calc'dfor C₂₁H₁₈ClNO₄S: C, 60.65; H, 4.36; N, 3.37 found: C, 60.55; H, 4.17;N, 3.34.

EXAMPLE 99

Synthesis of{5-Chloro-2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid (compound 99)

Step 1. Preparation of{5-Chloro-2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid methyl ester (compound 99A)

The title compound was prepared in the manner analogous to Example 1Fusing 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole and 20C. mp 120-121°C.; MS m/z 472 (M+1).Step 2. Preparation of{5-Chloro-2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-phenoxy}-aceticacid (compound 99)The title compound was prepared in the manner analogous to Example 1using 99A. mp 180-182° C.; IR (thin film) cm⁻¹: 1743, 1484, 1325, 1236,1165, 1111; 400 MHz ¹H NMR (DMSO-d₆) δ 13.03 (br s, 1H), 8.03 (d, 2H,J=8.1 Hz), 7.84 (d, 2H, J=8.3 Hz), 7.33 (s, 1H), 7.14 (s, 1H), 6.96 (s,1H), 4.71 (s, 2H), 4.23 (s, 2H), 2.07 (s, 3H); MS m/z 456 (M−1). Anal.Calc'd for C₂₀H₁₅ClF₃NO₄S: C, 52.47; H, 3.30; N, 3.06; found: C, 52.39;H, 3.02; N, 2.86.

EXAMPLE 100

Synthesis of2-[2-butyl-4-({4-[4-(trifluoromethyl)phenyl]phenyl}methylthio)phenoxy]aceticacid (compound 100)

Step 1. Preparation of 2-((1E)buta-1,3-dienyl)-1-methoxybenzene(compound 100A)

Methyltriphenylphosphonium bromide (42.9 g, 0.12 mol) was suspended in400 ml of anhydrous THF under nitrogen and cooled to −78° C. Sodiumhydride (60% in mineral oil, 6.0 g, 0.15 mol) was added portionwise. Thereaction mixture was allowed to warm up slowly to room temperature andstirred at the same temperature for 1 h, then 2-methoxycinnamaldehyde(16.2 g, 0.10 mol) in 200 ml of THF was added dropwise at roomtemperature, and stirred at the same temperature for 3 h. Water (200 ml)and diethyl ether (800 ml) were added. The organic layer was separated,dried over sodium sulfate, concentrated, and purified using normal phasechromatography to afford the title product. 400 MHz ¹H NMR (CDCl₃) δ7.48-6.56 (m, 7H), 5.32 (d, 1H), 5.16 (d, 11H), 3.84 (s, 3H).Step 2. Preparation of 2-butyl-1-methoxybenzene (compound 100B)

A mixture of the product from example 100A (12.8 g, 0.08 mol) andpalladium/carbon (10%, 50% water, 12 g) in 400 ml of ethyl acetate washydrogenated at 50 psi, at room temperature overnight, then filteredthrough Celite®, and concentrated to give 100B. 400 MHz ¹H NMR (CDCl₃) δ7.16 (m, 2H), 6.85 (m, 2H), 3.81 (s, 3H), 2.61 (m, 2H), 1.57 (m, 2H),1.38 (m, 2H), 0.92 (t, 3H).Step 3. Preparation of 2-butylphenol (compound 100C)

To a stirred solution of the product from example 100B (13.1 g, 0.08mol) in 400 ml of dichloromethane at −78° C. was added dropwise asolution of boron tribromide (100.2 g, 0.4 mol) in 200 ml ofdichloromethane. After the completion of addition of boron tribromide,the reaction mixture was maintained at −78° C. for 1 h, then allowed toreach room temperature and stirred at the same temperature overnight.The mixture was cooled to 0° C., and carefully quenched with 100 ml ofwater. The mixture was extracted with ethyl acetate, washed with brine,dried over sodium sulfate, and concentrated to give 100C. 400 MHz ¹H NMR(CDCl₃) δ 7.10 (m, 2H), 6.86 (m, 1H), 6.78 (d, 1H), 4.61 (brs, 1H), 2.61(m, 2H), 1.60 (m, 2H), 1.40 (m, 2H), 0.96 (t, 3H).Step 4. Preparation of (3-butyl-4-hydroxyphenyl)thiocarbonitrile(compound 100D)

The title compound was prepared in the manner analogous to Example 1Bwith the product from example 100C (2.38 g, 0.016 mol), sodiumthiocyanate (5.14 g, 0.063 mol), sodium bromide (1.63 g, 0.016 mol), andbromine (2.8 g, 0.017 mol) in methanol. 400 MHz ¹H NMR (CDCl₃) δ 7.30(m, 2H), 6.81 (d, 1H), 5.49 (brs, 1H), 2.60 (m, 2H), 1.59 (m, 2H), 1.38(m, 2H), 0.95 (t, 3H).Step 5. Preparation of methyl 2-(2-butyl-4-cyanothiophenoxy)acetate(compound 100E)

The title compound was prepared in the manner analogous to Example 1Cwith the product from example 100D (2.80 g, 0.014 mol), methylbromoacetate (2.28 g, 0.015 mol), and cesium carbonate (6.60 g, 0.020mol), in 100 ml of acetonitrile. 400 MHz ¹H NMR (CDCl₃) δ 7.38 (m, 2H),6.72 (d, 1H), 4.66 (s, 2H), 3.80 (s, 3H), 2.67 (m, 2H), 1.57 (m, 2H),1.38 (m, 2H), 0.98 (t, 3H).Step 6. Preparation of methyl 2-(2-butyl-4-sulfanylphenoxy) acetate(compound 100F)

The title compound was prepared in the manner analogous to Example 1Dwith the product from example 100E (2.79 g, 10.0 mol), dithiothreitol(3.08 g, 20.0 mmol), and 0.2 M potassium dihydrogenphosphate (15 ml) in60 ml of methanol. 400 MHz ¹H NMR (CDCl₃) δ 7.11 (m, 2H), 6.60 (d, 1H),4.61 (s, 2H), 3.81 (s, 3H), 3.36 (s, 1H), 2.63 (m, 2H), 1.57 (m, 2H),1.38 (m, 2H), 0.98 (t, 3H).Step 7. Preparation of methyl2-[2-butyl-4-({4-[4-(trifluoromethyl)phenyl]phenyl}methylthio)phenoxy]acetate(compound 100G)

The title compound was prepared in the manner analogous to Example 1Fusing 100F and 1-(bromomethyl)-4-[4-(trifluoromethyl)phenyl]benzeneprepared from and phosphorous tribromide and(4′-trifluoromethyl-biphenyl-4-yl)-methanol in a manner analogous toExample 3B. 400 MHz ¹H NMR (CDCl₃) δ 7.68 (m, 4H), 7.51 (d, 2H), 7.29(d, 2H), 7.15 (m, 2H), 6.60 (d, 1H), 4.62 (s, 2H), 4.04 (s, 2H), 3.79(s, 3H), 2.60 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 0.88 (t, 3H).Step 8. Preparation of2-[2-butyl-4-({4-[4-(trifluoromethyl)phenyl]phenyl}methylthio)phenoxy]aceticacid (compound 100)The title compound was prepared in the manner analogous to Example 1with the product from example 100G. mp 155-157° C.; 400 MHz ¹H NMR(DMSOd-₆) δ 7.88 (d, 2H), 7.80 (d, 2H), 7.65 (d, 2H), 7.38 (d, 2H), 7.17(dd, 1H), 7.09 (d, 1H), 6.79 (d, 1H), 4.65 (s, 2H), 4.17 (s, 2H), 2.50(m, 2H), 1.43 (m, 2H), 1.22 (m, 2H), 0.81 (t, 3H). MS m/z 473 (M−1).Anal. Calc'd for C₂₆H₂₅O₃SF₃: C, 65.81; H, 5.31; Found: C, 65.95; H,5.36.

EXAMPLE 101

Preparation of{6-methyl-8-[4-(4-trifluoromethyl-benzyloxy)-benzyl-sulfanyl]-chroman-5-yloxy}-aceticacid (compound 101)

Step 1.{6-methyl-8-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid methyl ester (compound 101A)

The title compound was prepared in the manner analogous to Example 1Fusing (8-mercapto-6-methyl-chroman-5-yloxy)-acetic acid methyl ester andthe product from Example 14B. MS m/z 533 (M+1).Step 2.{6-methyl-8-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-aceticacid (compound 101)2N KOH solution (5 ml) was added to a stirred slurry of the product fromExample 101A (0.4g, 0.75 mmol) in 2-3 ml of methanol, and the mixturewas heated briefly on a steambath until nearly clear, then stirred atroom temp. After 3 hours the mixture was diluted with 15-20 ml ofice-water and acidified with H₃PO₄. After 15 minutes the precipitate wasfiltered off, rinsed 3× with water, and dried to afford the titleproduct, 0.2g. 51% 400 MHz ¹H NMR (DMSO-d₆) δ 7.70 (d, 2H, J=8 Hz), 7.59(d, 2H, J=8 Hz), 7.18 (d, 2H, J=8.5 Hz), 6.88 (d, 2H, J=8.5 Hz), 6.83(s, 1H), 5.14 (s, 2H), 4.21 (s, 2H), 4.06 (t, 2H, J=4.9Hz), 3.95 (s,2H), 2.63 (t, 2H, J=6.3Hz), 2.03 (s, 3H), 1.79 (quint, 2H); MS m/z 517(M−1).

EXAMPLE 102

Preparation of{4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-aceticacid (compound 102)

Step 1.{4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-aceticacid methyl ester (compound 102A)

The title compound was prepared in the manner analogous to Example 1Fusing (4-mercapto-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acidmethyl ester and the product from Example 42C; recrystallization frommethanol afforded the title compound. MS m/z 478 (M+1).Step 2.{4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-aceticacid (compound 102)The title compound was prepared in the manner analogous to Example 1using the product from Example 102A. mp 167-170° C.; 400 MHz ¹H NMR(DMSO-d₆) δ 8.01 (d, 2H, J=8 Hz), 7.83 (d, 2H, J=8.3 Hz), 7.14 (d, 2H,J=8.5 Hz), 7.07 (s, 1H), 6.58 (d, 2H, J=8.8 Hz), 4.56 (s, 2H), 4.07 (s,2H), 2.64 (m, 2H), 2.53 (m, 2H), 1.60 (m, 4H); MS m/z 464 (M+1).The compounds of the present invention can also be prepared usingcombinatorial chemistry methods. In particular, compounds of Examples103-134 were prepared using combinatorial chemistry analogous to thatpreviously described in Examples 1-102. The combinatorial chemistrymethods useful in the present invention include those where an activatedalcohol is contacted with a thiol followed by saponification of theresulting ester to afford the desired products. Such methods can beillustrated by previously described Scheme 1 where compound D is anexemplary thiol, compound Y is an exemplary activated alcohol, andcompound F is an exemplary desired product.

Example No. Name MS m/z 103(4-{2-Butyl-5-chloro-1-[4-(1-cyano-cyclopentyl)- 552.37benzyl]-1H-imidazol-4-ylmethylsulfanyl}-2-methyl- phenoxy)-acetic acid104 [4-(5-Biphenyl-4-yl-2-thiopen-2-yl-4,5-dihydro- 546.33oxazol-4-ylmethylsulfanyl)-5-methoxy-2-methyl- phenoxy]-acetic acid 105{4-[2-(4-Bromo-phenoxy)-ethylsulfanyl]-2,6- 451.33dimethyl-phenoxy}-acetic acid 106[4-(3-{2-[4-(2-Diethylamino-ethoxy)-phenyl]- 578.43benzimidazol-1-yl]-propylsulfanyl)-5-methoxy-2- methyl-phenoxy]-aceticacid 107 [4-(5-Biphenyl-4-yl-2-thiophen-2-yl-4,5-dihydro- 516.31oxazol-4-ylmethylsulfanyl)-2-methyl-phenoxy]- acetic acid 108(4-{2-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-7-yl]- 451.24ethylsulfanyl}-2-methyl-phenoxy)-acetic acid 109{2-Methyl-4-[2-(5-phenyl-naphthalen-1-yloxy)- 443.3ethylsulfanyl]-phenoxy}-acetic acid 110[2-Methyl-4-(3-phenoxy-benzylsulfanyl)-phenoxy]- 379.23 acetic acid 111[2,5-Dimethyl-4-(5-p-tolyl-1,3,4-oxadiazol-2- 385.22ylmethylsulfanyl)-phenoxy]-acetic acid 112[2-Methyl-4-(4-pyrazol-1-yl-benzylsulfanyl)- 355.2 phenoxy]-acetic acid113 [2-Methyl-4-(5-methyl-3-phenyl-isoxazol-4- 370.2ylmethylsulfanyl)-phenoxy]-acetic acid 114[4-(Biphenyl-2-ylmethylsulfanyl)-2-methyl- 363.2 phenoxy]-acetic acid115 {4-[5-(4-Chloro-phenyl)-isoxazol-3- 390.16ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid 116[2-Methyl-4-(5-p-tolyl-1,3,4-oxadizol-2- 371.19ylmethylsulfanyl)-phenoxy]-acetic acid 117{4-[3-(4-Chloro-phenyl)-1,2,4-oxadiazol-5- 391.14ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid 118[2,5-Dimethyl-4-(4-pyrazol-1-yl-benzylsulfanyl)- 369.2 phenoxy]-aceticacid 119 [4-(Biphenyl-2-ylmethylsulfanyl)-2,5-dimethyl- 377.19phenoxy]-acetic acid 120[4-(4-Benzyloxy-benzylsulfanyl)-5,6,7,8-tetrahydro- 433.41naphthalen-1-yloxy]-acetic acid 121[4-(4-Benzyloxy-benzylsulfanyl)-2,6-dimethyl- 407.39 phenoxy]-aceticacid 122 [4-(4-Benzyloxy-benzylsulfanyl)-2,5-dimethyl- 407.38phenoxy]-acetic acid 123 [4-(4-Benzyloxy-benzylsulfanyl)-2-methyl-393.38 phenoxy]-acetic acid 124[4-(4-Benzyloxy-benzylsulfanyl)-phenoxy]-acetic 379.35 acid 125[4-(Biphenyl-4-ylmethylsulfanyl)-5,6,7,8-tetrahydro- 403.4naphthalen-1-yloxy]-acetic acid 126[4-(Biphenyl-4-ylmethylsulfanyl)-2,6-dimethyl- 377.38 phenoxy]-aceticacid 127 [4-(Biphenyl-4-ylmethylsulfanyl)-2,5-dimethyl- 377.37phenoxy]-acetic acid 128[4-(Biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic 349.32 acid 129{4-[3-(2-Fluoro-phenoxy)-benzylsulfanyl]-2,6- 411.2dimethyl-phenoxy}-acetic acid 130[4-(2-{4-[2-(3-Chloro-4-cyclohexyl-phenyl)-ethyl]- 531.31piperazin-1-yl}-ethylsulfanyl)-2-methyl-phenoxy]- acetic acid 131[5-Methoxy-2-methyl-4-(2-{4-[2-(3-phenyl- 561.37benzofuran-7-yl)-ethyl]-piperazin-1-yl}- ethylsulfanyl)-phenoxy]-aceticacid 132 {4-[2-(2,6-Diphenyl-piperidin-1-yl)-ethylsulfanyl]- 492.315-methoxy-2-methyl-phenoxy}-acetic acid 133[2-Methyl-4-(2-{4-[2-(3-phenyl- 531.32benzofuran-7-yl)-ethyl]-piperazin-1-yl)- ethylsulfanyl)-phenoxy]-aceticacid 134 {4-[2-(2,6-Diphenyl-piperidin-1-yl)-ethylsulfanyl]- 462.252-methyl-phenoxy}-acetic acidThe preparation of Examples 103-134 is further described below.Preparation of Thiols used in Combinatorial Methods

Thiol WW

Preparation of 2,5Dimethyl-4-thiocyanato-phenol (compound WWA)

The title compound was prepared in a manner analogous to compound 1B.400 MHz ¹H NMR (DOMSO-d₆) δ 10.0 (s, 1H), 7.35 (s, 1H), 6.73 (s, 1H),2.3 (s, 3H), 2.04 (s, 3H); MS m/z 180 (m+1).

Preparation of (2,5-Dimethyl-4-thiocyanato-phenoxy)-acetic acid methylester (compound WWB)

The title compound was prepared from compound WWA in a manner analogousto compound 1C. 400 MHz ¹H NMR (DMSO-d₆) δ 7.07 (s, 1H), 6.50 (s, 1H),4.56 (s, 2H), 3.76 (s, 3H), (s, 1H), 2.26 (s, 3H), 2.17 (s, 3H); MS m/z252 (m+1).

Preparation of (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid methylester (compound WW)

The title compound was prepared from compound WWB in a manner analogousto compound 1D. 400 MHz ¹H NMR (DMSO-d₆) δ 7.07 (s, 1H), 6.50 (s, 1H),4.56 (s, 2H), 3.76 (s, 3H), 3.07 (s, 1H), 2.26 (s, 3H), 2.17 (s, 3H); MSm/z 227 (M+1).

Thiol XX

Preparation of 2,6-Dimethyl-4-thiocyanato-phenol (compound XXA)

Compound XXA was prepared from 2,6-dimethylphenol in a similar manner asdescribed for compound 1B. 400 MHz ¹H NMR (DMSO-d₆) δ 8.96 (s, 1H), 7.22(s, 2H), 2.13 (s, 6H).

Preparation of (2,6-Dimethyl-4-thiocyanato-phenoxy)-acetic acid methylester (compound XXB)

Compound XXB was prepared from compound XXA in a similar manner asdescribed for compound 1C to give 2.5 g (46%) of the title compound pureenough for subsequent use 400 MHz ¹H NMR (DMSO-d₆) δ 7.11 (s, 2H), 4.41(s, 2H), 3.63 (s, 3H), 2.14 (s, 6H).

Preparation of (4-Mercapto-2,6-dimethyl-phenoxy)-acetic acid methylester (compound XX)

Compound XX was prepared from compound XXB in a similar manner asdescribed for compound 1D to give, after purification by flash columnchromatography (gradient elution: 100% hexanes to 30% EtOAc/hexanes),1.8 g (82%) of the title compound. 400 MHz ¹H NMR (DMSO-d₆) δ 6.90 (s,2H), 5.51 (s, 1H), 4.39 (s, 2H), 3.66 (s, 3H), 2.10 (s, 6H); MS m/z 225(M−1).

Thiol YY

Preparation of 4-Thiocyanato-5,6,7,8-tetrahydronaphthalen-1-ol (compoundYYA)

5,6,7,8-Tetrahydro-naphthalen-1-ol (1 g, 6.8 mmol) was dissolved in 25ml acetonitrile. Sodium thiocyanate (1.76 g, 22 mmol) and sodium bromide(0.7 g, 6.8 mmol) were added and stirred for 5 minutes at ambienttemperature. Bromine (1.2 g, 7.48 mmol) was added drop wise over 5minutes. The orange solution was allowed to stir two hours. Brine wasadded and the crude product was extracted twice into ethyl acetate. Thecombined organic extracts were washed once with brine, dried overanhydrous sodium sulfate, decanted and concentrated. Normal phasechromatography afforded the title product, 1.28 g, 92%. 400 MHz ¹H MR(DMSO-d₆) δ 11.1 (s, 1H), 7.40 (d, 1H, J=8.8 Hz), 6.61 (d, 1H, 8.8 Hz),2.78 (m, 2H), 2.59 (m, 2H), 1.70 (m, 4H). MS m/z 278 (m+1)Preparation of(4-Thiocyanato-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid methylester (compound YYB)

The title compound was prepared in the manner analogous to example 1Cutilizing compound YYA. 400 MHz ¹H NMR (DMSO-d₆) δ 7.4 (d, 1H, J=8.8Hz), 6.80 (d, 1H, 8.8 Hz), 4.84 (s, 2H), 3.64 (s, 3H), 2.78 (m, 2H),2.59 (m, 2H), 1.70 (m, 4H). MS m/z 278 (m+1).Preparation of (4-Mercapto-5,6,7,8tetrahydro-naphthalen-1-yloxy)-aceticacid methyl ester (compound YY)

The title compound was prepared in the manner analogous to example 1Dutilizing compound YYB. 400 MHz ¹H NMR (DMSO-d₆) δ 7.08 (d, 1H, J=8.8Hz), 6.55 (d, 1H, 8.8 Hz), 4.71 (s, 1H), 4.70 (s, 2H), 3.63 (s, 3H),2.45 (m, 2H), 2.44 (m, 2H), 1.65 (m, 4H). MS m/z 253 (M+1).

Thiol ZZ

Preparation of 4-Thiocyanato-phenol (compound ZZA)

The title compound was prepared in the manner analogous to Example 1Busing phenol. MS m/z 152 (M+1)

Preparation of [(4-Thiocyanato-phenoxy)-acetic acid methyl ester(compound ZZB)

The title compound was prepared in the manner analogous to Example 1Cusing ZZA. MS m/z 224 (M+1)

Preparation of (4-Mercapto-phenoxy)-acetic acid methyl ester (compoundZZ)

The title compound was prepared in the manner analogous to Example 1Dusing ZZB. MS m/z 197 (M−1)

Preparation of Examples 103-134

Alcohol Preparation:

The appropriate alcohols in the salt form (0.65 mmol) were dissolved in3.0 mL of low water MeOH. MP-CO₃ (3.21 mmol/g, 3.70 equivalents toalcohol, 2.41 mmol) was then added to each vial containing the alcoholand shaken at ambient temperature for 3 h. The samples were thenfiltered into tared vials and concentrated.Alcohol Activation:Each alcohol sample was then diluted to 0.15M with DCM and 1.0 ML ofeach delivered to a reaction tube. PS-morpholine (4.0 mmol/g, 2equivalents to alcohol, 0.3 mmol) and 25 μL methanesulfonyl chloride wasthen added to each reaction tube. The reaction tubes were shaken atambient temperature for 16 h. The samples were then filtered intocollection tubes, the resin rinsed with two 1.0 mL aliquots of DCM, andconcentrated.Alkylation:Examples 103-134 were synthesized in the following fashion using eitherthe thiol products 2C, 1D, WW, XX, YY or ZZ and the appropriateactivated alcohol or alkyl halide. Each thiol was diluted to 0.15M withCH₃CN and each activated alcohol diluted to 0.15M with CH₃CN. 1.0 mLaliquots of each thiol (0.15 mmol) and 1.0 mL aliquots of each activatedalcohol (1.0 equivalents, 0.15 mmol) were then delivered to a reactiontube and 100 mg Cs₂CO₃ (2 equivalents, 0.3 mmol) was added. The reactiontubes were shaken at 60° C. for 2.5 h. The reaction mixtures werefiltered into collection tubes, the resin rinsed with two 1.0 mLaliquots of CH₃CN, and concentrated.Saponification:Examples 103-134 were synthesized in the following fashion using theproducts from the alkylation step discussed above. Each alkylationproduct was diluted with 3.0 mL of 0.5M LiOH in 4:1 methoxyethanol:H₂Oshaken at 60° C. for 4 h and cooled to ambient temperature. To eachreaction, was then added 1.0 mL 1N HCl and 1.0 mL brine. Each reactionwas extracted twice with 2.0 mL EtOAc, and the organic layersconcentrated to afford the desired products.

Biological Assays

The compounds of the present invention have demonstrated PPAR modulatingactivity in the standard assays commonly employed by those skilled inthe art. Accordingly, such compounds and formulations comprising suchcompounds are useful for suppressing appetite, modulating leptin, andtreating, preventing or controlling hypercholesterolemia, dyslipidemia,obesity, eating disorders, hyperglycemia, atherosclerosis,hypertriglyceridemia, hyperinsulinemia and diabetes.

A. Selectivity Measurements

1. Test A. Transient Transfections Assay using the HepG2Hepatoma CellLine.

HepG2 cells were transiently transfected with an expression plasmidsencoding hPPARα, hPPARβ or mPPARγ chimeric receptors and a reportercontaining the yeast upstream activating sequence (UAS) upstream of theviral E1B promoter controlling a luceriferase reporter gene. Inaddition, the plasmid pRSVβ-gal was used to control the transfectionefficiency, HepG2 cells were grown in DMEM supplemented with 10% FBS and1 μM non-essential amino acid. On the first day, cells were split into100 mm dishes at 2.5×10⁸/dish and incubated overnight at 37° C./5% CO₂.On the second day the cells were transiently transfected with plasmidDNA encoding a chimeric receptor, the luciferase reporter gene; andβ-gal. For each 100 mm dish, 15 μg of lucifease reporter (PG5E1b) DNA,15 μg of Gal4-PPAR chimeric receptor DNA, and 1.5 μg of β-gal plasmidDNA were mixed with 1.4 ml of opti-MEM in the tube. 28 μl ofLipoFectamine-2000 reagent was added to 1.4 ml of opti-MEM in the tube,and incubate for 5 min at RT. The diluted LipoFectamine-2000 reagent wascombined with the DNA mixture, and incubate for 20 min at RT. Afterfresh medium was added to each 100 mm dish of cells, 2.8 ml ofLipofectamine2000-DNA mixture was added dropwise to the 100 mm dishcontaining 14 ml of medium, and incubate 37° C. overnight. On day threecells were trypsinized off the 100 mm dishes and re-plated on 96 wellplates. Cells were plated at 2.5×10⁴ cells per well in 150 μl of mediaand 50 μl of compound diluted by media was added. The test compoundadded were in the range from 50 μM to 50 pM. After addition ofcompounds, the plates were incubated at 37° C. for 24 hours. Subseqentlycells were washed with once with 100 μl of PBS, lysed, and processed formeasuring luciferase and β-gal activity using Dual-Light luciferase kitfrom Tropix®, according to the manufacturer's recommendations, on anEG&G Bethold MicroLumat LB96P luminometer. EC₅₀ values were obtainedusing the GraphPad Prism™ program. Surprisingly, the compounds of thepresent invention exhibit activity for both PPARα and PPARβ. Compoundsof the present invention exhibited a range of Hep G2-hBeta EC₅₀'s(“EC₅₀β”) and Hep G2-hAlpha EC₅₀'s (“EC₅₀α”) from greater than zero toabout 20 μM. Specifically, as shown in Table 1, the Hep G2-hBeta EC₅₀'sand Hep G2-hAlpha EC₅₀'s for the compounds of the present invention fallwithin the following 6 groups:

I) >0-300 nM

II) >300-500 nM

III) >500-1000 nM

IV) >1000-2000 nM

V) >2000-5000 nM

VI) >5000 nM

TABLE 1 Ec₅₀β nM EC₅₀α nM Compound (Group) (Group) 1 I I 3 I V 4 I I 5IV — 7 I I 9 I I 10 I II 11 I III 12 I — 14 I I 15 I — 16 I I 17 IV V 18I VI 19 I I 20 I V 21 I I 22 IV III 23 I I 25 V IV 26 I — 27 V III 28 IVIV 29 I I 30 IV IV 31 VI IV 32 II IV 33 IV IV 34 I I 35 II I 36 V I 37 I— 38 I — 39 I — 40 III — 41 I V 42 I V 43 I III 44 III VI 45 I — 46 I I47 VI — 48 I V 49 I II 50 V — 51 V — 52 I III 53 I IV 54 II — 57 V IV 58V — 59 IV VI 60 VI — 61 II — 62 IV VI 63 I V 64 VI — 65 VI — 66 VI — 67I — 68 IV — 69 V — 70 III — 71 III — 72 IV — 73 I V 74 I V 75 III — 76IV — 77 II — 78 II — 79 II VI 80 IV — 81 I VI 84 II VI 85 IV — 87 V — 88VI — 89 IV — 90 III — 91 V — 92 I I 93 III — 97 III VI 98 V — 99 II —100 III —B. Effect of PPAR Modulators on Lipid and Human Apoprotein A1Concentrations in the hApoA1 Transgenic Mouse

Mice, transgenic for human apoA1, were purchased from Jacksonlaboratories. All animals were allowed normal chow (Ralston-Purina) andwater ad libitum in temperature controlled rooms, under a 12-h light,12-h dark cycle beginning with lights on at 6 AM. During the treatmentphase of the study the mice were dosed daily between 6 and 9 AM by oralgavage using a suspension vehicle of 1.5% carboxymethyl-cellulose plus0.2 percent Tween-20 (CMC/Tween) containing the specifid compounds.Control animals received vehicle alone. Vehicle volume represented 0.25percent of body weight. Under anesthesia, tail blood was obtained weeklyin the morning at the indicated days of study. At termination, tissuesamples (liver, intestine, fat, and muscle) were taken to study effectson genes effecting lipid metabolism. Each of the compounds of thepresent invention that were tested effected a significant increase inHDL over the values observed for the control animals. Furthermore, thesecompounds resulted in triglyceride levels which were lower than observedin controls. Componds of the present invention tested in the hApoAItransgenic mouse model showed a range of HDL-c elevation andtriglyceride lowering when dosed at 30 mg/kg/day. For instance, Example4 raised HDL-c 97% and lowered triglycerides 65 % relative to thecontrol population, Example 6 raised HDL-c 24% and lowered triglycerides59 % relative to the control population, and Example 3 raised HDL-c 9%and lowered triglycerides 70% relative to the control population.

5 C. Effect of Compounds of the Invention on Insulin Resistant orDiabetic Cynomolgus Monkeys

Cynomolgus monkeys that were either insulin resistant or diabetic (typeII) were treated for eight weeks with[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid in a rising dose fashion (0.1 to 1 mg/kg). Plasma was sampledbi-weekly and analyzed for glycemics and leptin. Body weight was alsomeasured at various time points across the study. The diabetic monekymean body weight data is presented in Table 2 and the insulin resistantmonkey mean body weight data is presented in Table 3.

TABLE 2 Diabetic Monkey Mean Body Weight Mean −7 wk −4 wk Baseline 2 wk5 wk 7 wk 8 wk Diab Ctl 8.10 8.05 8.08 8.17 8.18 8.17 8.19 Mean Diab Ctl3.77 3.77 3.77 3.74 3.70 3.70 3.64 StDev Diab Ctl 1.89 1.88 1.89 1.871.85 1.85 1.82 SEM Diab Txt 8.84 8.91 8.87 8.75 8.37 8.08 7.80 Mean DiabTxt 3.73 3.68 3.70 3.61 3.52 3.34 3.20 StDev Diab Txt 1.32 1.30 1.311.28 1.24 1.18 1.13 SEM IR = insulin resistant, Diab = diabetic, Ctl =control, Txt = experimental, StDev = standard deviation, SEM = standarderror of the mean

TABLE 3 Insulin Resistant Monkey Mean Body Weight Mean −7 wk −4 wkBaseline 2 wk 5 wk 7 wk 8 wk IR Ctl Mean 6.18 6.15 6.17 6.04 6.00 5.945.91 IR Ctl StDev 3.48 3.43 3.46 3.22 3.19 3.16 3.17 IR Ctl SEM 1.741.72 1.73 1.61 1.60 1.58 1.59 IR Txt Mean 5.25 5.32 5.29 5.26 5.04 4.914.71 IR Txt 3.17 3.22 3.19 3.42 3.40 3.34 3.20 StDev IR Txt SEM 0.950.97 0.96 1.03 1.03 1.01 0.96 IR = insulin resistant, Diab = diabetic,Ctl = control, Txt = treated, StDev = standard deviation, SEM = standarderror of the mean

Plasma leptin values, presented as baseline values vs. 8-week treatment,were determined by ELISA and are presented in Table 4. The effect of[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid on plasma leptin values in diabetic and insulin resistant obesecynomolgus monkeys is demonstrated by the lesser increase in plasmaleptin values seen in the treated animals.

The amount of exogenous insulin the diabetic monkeys received tomaintain proper glucose levels, the exogenous insulin requirement, isalso presented in Table 4 as baseline values vs. 8-week treatment. Bydefinition, insulin resistant monkeys are not yet diabetic and do notreceive exogenous insulin. A reduction in exogenous insulin requirementsis a measure of improved insulin sensitivity and glucose control.

TABLE 4 Leptin and Exogenous Insulin Pre-Treatment Post-TreatmentExogenous Insulin Requirement (u/day) Diabetic Controls 89 ± 71 101 ± 73Diabetic Treated 66 ± 16 18 ± 4 Leptin (ng/ml) Diabetic Controls 6.55 ±1.38 18.83 ± 0.24 Diabetic Treated 7.22 ± 0.93 10.89 ± 2.7 InsulinResistant Controls 9.85 ± 0.45 13.60 ± 3.45 Insulin Resistant Treated7.33 ± 1.16 5.73 ± 2.14

Formulations

The compounds of the present invention can be administered alone or incombination with one or more therapeutic agents. These include, forexample, other agents for the treatment, control, or prevention ofhypercholesteremia, dyslipidemia, obesity, hyperglycemia,hypercholesteremia, atherosclerosis, hypertriglyceridemia, andhyperinsulinemia. The compounds of the present invention can beadministered alone or in combination with one or more therapeutic agentsfor the supression of appetite and modulation of leptin.

The compounds are thus well suited to formulation for convenientadministration to mammals for the prevention and treatment of suchdisorders.

The following examples further illustrate typical formulations providedby the invention.

Formulation 1 Ingredient Amount compound of Formulas I-V 0.5 to 800 mgsodium benzoate 5 mg isotonic saline 1000 mL

The above ingredients are mixed and dissolved in the saline for IVadministration to a patient.

Formulation 2 Ingredient Amount compound of Formulas I-V 0.5 to 800 mgcellulose, microcrystalline 400 mg stearic acid 5 mg silicon dioxide 10mg sugar, confectionery 50 mg

The ingredients are blended to uniformity and pressed into a tablet thatis well suited for oral administration to a patient.

Formulation 3 Ingredient Amount compound of Formulas I-V 0.5 to 800 mgstarch, dried 250 mg magnesium stearate 10 mg

The ingredients are combined and milled to afford material suitable forfilling hard gelatin capsules administered to a patient.

Formulation 4 Ingredient Amount % wt./(total wt.) compound of FormulasI-V  1 to 50 Polyethylene glycol 1000 32 to 75 Polyethylene glycol 400016 to 25

The ingredients are combined via melting and then poured into moldscontaining 2.5 g total weight.

While embodiments of the invention have been illustrated and described,it is not intended that these embodiments illustrate and describe allpossible forms of the invention. Rather, the words used in thespecification are words of description rather than limitation, and it isunderstood that various changes may be made without departing from thespirit and scope of the invention.

1. A compund of formula (I):

and pharmaceutically acceptable salts thereof, wherein: X⁰ and S; X¹ isabsent; O, S, —CH₂—, —CH₂—CH₂—, or —CH═CH—; Ar¹ and Ar² are eachindependently unsubstituted or substituted phenyl or pyridinyl;

 is absent; R¹ and R² are selected from hydrogen, lower alkyl, loweralkoxy, haloalkyl, —O—(CH₂)_(m)CF₃, halogen, nitro, cyano, —OH, —SH or—CF₃; R³ and R⁴ are selected from hydrogen, lower alkyl, lower alkoxy,haloalkyl, —O—(CH₂)_(m)CF₃, halogen, nitro, cyano, —OH, —SH or —CF₃;provided that at least one of R₁-R₄ is H, lower alkyl, lower alkoxy,haloalkyl, —O—(CH₂)_(m)CF₃, halogen, nitro, cyano, —OH, —SH or —CF₃; mis 0 to 5; q is 0 to 1; and r is 0 to
 1. 2. The compund of claim 1,wherein X¹ is absent or 0; Ar¹ and Ar² are each independentlyunsubstituted or substituted phenyl or pyridinyl; R¹ is hydrogen; R² islower alkyl, lower alkoxy, haloalkyl, —O—(CH₂)_(m)CF₃, halogen, nitro,cyano, —OH, —SH or —CF₃; R³ is lower alkyl, lower alkoxy, haloalkyl,—O—(CH₂)_(m)CF₃, halogen, nitro, cyano, —OH, —SH or —CF₃; R⁴ ishydrogen, lower alkyl, lower alkoxy, haloalkyl, —O—CH₂)_(m)CF₃, halogen,nitro, cyano, —OH, —SH or —CF₃; m is 0 to 5; q is 1; and r is 0 to
 1. 3.The compund of claim 1, wherein X¹ is absent; Ar¹ is phenyl; Ar² issubstituted phenyl or pyridinyl; R¹ is hydrogen; R² is lower alkyl,lower alkoxy, haloalkyl, —O—(CH₂)_(m)CF₃, —OH or —SH; R³ is lower alkylor haloalkyl; R⁴ is hydrogen; m is 0 to 5; q is 1; and r is
 0. 4. Thecompund of claim 1, wherein X¹ is absent or 0; Ar¹ is phenyl; Ar² issubstituted phenyl; R¹ is hydrogen; R² is lower alkoxy; R³ is loweralkyl; R⁴ is hydrogen; q is 1; and r is 0 to
 1. 5. The compund of claim1, wherein X¹ is absent or 0; Ar¹ is phenyl; Ar² is substituted phenyl;R¹ is hydrogen; R² is methoxy; R³ is methyl; R⁴ is hydrogen; q is 1; andr is 0 to
 1. 6. The compound of claim 1, wherein q is
 1. 7. The compoundof claim 1, wherein Ar¹ is substituted or unsubstituted phenyl.
 8. Thecompound of claim 1, wherein Ar² is 4-trifluoromethylphenyl.
 9. Thecompound of claim 1, wherein: R¹, R², R³, and R⁴ are selected fromhydrogen, alkyl, or alkoxy.
 10. The compound of claim 1, wherein: R² andR³ are hydrogen; and R¹ and R⁴ are alkyl or alkoxy.
 11. The compound ofclaim 1, wherein: R¹ is alkyl; R² and R³ are hydrogen; and R⁴ is alkoxy.12. The compound of claim 1, wherein: R¹ is methyl, ethyl, isopropyl,n-propyl, t-butyl, n-butyl, or isobutyl; R² and R³ are hydrogen; and R⁴is methyoxy, ethoxy, isopropoxy, n-propoxy, t-butoxy, n-butoxy, orisobutoxy.
 13. A compound selected from:[4-(Biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methylphenoxy]-acetic acid;[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;[4-(2′,4′-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid;[5-Methoxy-2-methyl-4-(3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;[4-(4′-Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-aceticacid;[5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy]-aceticacid;[5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid;{{-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-phenoxy}-aceticacid;{5-Methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethylsulfanyl]-phenoxy}-aceticacid;[3-Methoxy-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;(4-{4-[2-(3-Fluoro-phenyl)-vinyl]benzylsulfanyl}-5-methoxy-2-methyl-phenoxy)-aceticacid;[5-Methoxy-2-methyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-aceticacid;[5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-phenoxy]-aceticacid; and pharmaceutically acceptable salts thereof.
 14. Apharmaceutical composition comprising a compound of claim 1 or apharmaceutically acceptable salt thereof admixed with a carrier,diluent, or excipient.
 15. A method of treating or controllingnon-insulin dependent diabetes mellitus in a mammal comprisingadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of claim 1 formula (I):

or a pharmaceutically acceptable salt thereof wherein: X ⁰ is S; X ¹ isabsent, O, S, —CH ₂ —, —CH ₂ —CH ₂ —, or —CH═CH; Ar ¹ and Ar ² are eachindependently unsubstituted or substituted phenyl or pyridinyl;

is absent; R ¹ and R ² are selected from hydrogen, lower alkyl, loweralkoxy, haloalkyl,—O—(CH ₂)_(m) CF ₃ , halogen, nitro, cyano, —OH, —SHor —CF ₃; R ³ and R ⁴ are selected from hydrogen, lower alkyl, loweralkoxy, haloalkyl,—O—(CH ₂)_(m) CF ₃ , halogen, nitro, cyano, —OH, —SHor —CF ₃ , provided that at least one of R ₁-R ₄ is H, lower alkyl,lower alkoxy, haloalkyl,—O—(CH ₂)_(m) CF ₃ , halogen, nitro, cyano, —OH,—SH or —CF ₃ ; m is 0 to 5; q is 0 to 1; and r is 0 to 1 .
 16. A methodof treating or controlling obesity in a mammal comprising adminsiteringto the mammal in need thereof a therapeutically effective amount of acompound of claim 1 formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X ⁰ is S; X ¹ isabsent, O, S, —CH ₂ —, —CH ₂ —CH ₂ —, or —CH═CH; Ar ¹ and Ar ² are eachindependently unsubstituted or substituted phenyl or pyridinyl;

is absent; R ¹ and R ² are selected from hydrogen, lower alkyl, loweralkoxy, haloalkyl,—O—(CH ₂)_(m) CF ₃ , halogen, nitro, cyano, —OH, —SHor —CF ₃; R ³ and R ⁴ are selected from hydrogen, lower alkyl, loweralkoxy, haloalkyl,—O—(CH ₂)_(m) CF ₃ , halogen, nitro, cyano, —OH, —SHor —CF ₃ , provided that at least one of R ₁-R ₄ is H, lower alkyl,lower alkoxy, haloalkyl,—O—(CH ₂)_(m) CF ₃ , halogen, nitro, cyano, —OH,—SH or —CF ₃ ; m is 0 to 5; q is 0 to 1; and r is 0 to 1 .
 17. A methodof treating or controlling eating disorders in a mammal comprisingadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of claim
 1. 18. A method of supressing appetite ina mammal comprising administering to the mammal in need thereof atherapeutically effective amount of a compound of claim
 1. 19. A methodof modulating leptin levels in a mammal comprising administering to themammal in need thereof a therapeutically effective amount of a compoundof claim
 1. 20. A method of treating or controlling hyperglycemia in amammal comprising administering to the mammal in need thereof atherapeutically effective amount of a compound of claim
 1. 21. A methodof treating or controlling hyperinsulinemia in a mammal comprisingadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of claim
 1. 22. A method of treating a patientexhibiting glucose disorders associated with circulatingglucocorticoids, growth hormone, catecholamines, glucagon, orparathyroid hormone, comprising administering to the patient atherapeutically effective amount of a compound of claim
 1. 23. A methodof treating non-insuline dependent diabetes mellitus in a patientcomprising administering to the patient in need of treatment acomposition according to claim
 14. 24. A method of treating metabolicsyndrome in a patient comprising administering to the patient in need oftreatment a composition according to claim 14 comprising a compound offormula (I):

or a pharmaceutically acceptable salt thereof, wherein: X ⁰ is S; X ¹ isabsent, O, S, —CH ₂ —, —CH ₂ —CH ₂ —, or —CH═CH; Ar ¹ and Ar ² are eachindependently unsubstituted or substituted phenyl or pyridinyl;

is absent; R ¹ and R ² are selected from hydrogen, lower alkyl, loweralkoxy, haloalkyl,—O—(CH ₂)_(m) CF ₃ , halogen, nitro, cyano, —OH, —SHor —CF ₃; R ³ and R ⁴ are selected from hydrogen, lower alkyl, loweralkoxy, haloalkyl,—O—(CH ₂)_(m) CF ₃ , halogen, nitro, cyano, —OH, —SHor —CF ₃ , provided that at least one of R ₁-R ₄ is H, lower alkyl,lower alkoxy, haloalkyl,—O—(CH ₂)_(m) CF ₃ , halogen, nitro, cyano, —OH,—SH or —CF ₃ ; m is 0 to 5; q is 0 to 1; and r is 0 to 1; and apharmacuetically acceptable carrier, diluent or vehicle.